Crispr/cas9 therapies for correcting duchenne muscular dystrophy by targeted genomic integration

ABSTRACT

Disclosed herein arm CRISPR/Cas-based genome editing compositions and methods for treating Duchenne Muscular Dystrophy by restoring dystrophin function. The CRISPR/Cas-based genome editing systems may include a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, a Cas protein or a fusion protein comprising the Cas protein, and a donor sequence comprising a fragment of a wild-type dystrophin gene.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 63/016,282, fled Apr. 27, 2020, and U.S. Provisional Patent Application No. 63/160,551, filed Mar. 12, 2021, each of which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant R01AR069085 awarded by the National Institutes of Health. The government has certain rights in the invention.

FIELD

The present disclosure is directed to CRISPR/Cas-based genome editing compositions and methods for treating Duchenne Muscular Dystrophy by restoring dystrophin function.

INTRODUCTION

Duchenne muscular dystrophy (DMD) is the most prevalent lethal heritable childhood disease occurring in ˜1:5000 newborn males. Progressive muscle weakness leading to mortality in patients' mid-20s is a result of mutations in the dystrophin gene. In most cases (˜60%), the mutations consist of deletions in one or more of the 79 exons from the dystrophin gene, leading to disruption of the reading frame. Previous therapeutic strategies typically aim to generate expression of a truncated but partially functional dystrophin protein that recapitulates a genotype corresponding to Becker muscular dystrophy, which is associated with milder symptoms relative to DMD. For example, several groups have adapted the CRISPR/Cas9 technology for gene editing in cultured human DMD cells and the mdx mouse model of DMD to restore the dystrophin reading frame by deleting specific exons. However, there remains a need to develop gene editing strategies to restore the complete, fully functional dystrophin protein.

SUMMARY

In an aspect, the disclosure relates to a CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.

In a further aspect, the disclosure relates to a CRISPR/Cas-based genome editing system comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.

Another aspect of the disclosure provides a CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition. The composition may include (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.

Another aspect of the disclosure provides a CRISPR/Cas-based genome editing system. The system may include (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene: (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.

In some embodiments, the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene. In some embodiments, the gRNA hybridizes to a target sequence within the polynucleotide sequence of SEQ ID NO: 128 or SEQ ID NO: 156. In some embodiments, the donor sequence comprises exon 52 of the wild-type dystrophin gene. In some embodiments, donor sequence comprises the polynucleotide sequence of SEQ ID NO: 53. In some embodiments, the fragment of the wild-type dystrophin gene is flanked on both sides by a gRNA spacer and/or a PAM sequence. In some embodiments, the gRNA targets an intron that is between exon 51 and exon 52 of the mutant dystrophin gene. In some embodiments, the donor sequence comprises multiple exons of the wild-type dystrophin gene or a functional equivalent thereof.

In some embodiments, the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of the wild-type dystrophin gene or a functional equivalent thereof. In some embodiments, the donor sequence comprises exons 52-79 of the wild-type dystrophin gene or a functional equivalent thereof. In some embodiments, the donor sequence comprises exons 45-79 of the wild-type dystrophin gene or a functional equivalent thereof. In some embodiments, exon 52 of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene, or wherein exon 52 of the mutant dystrophin gene is deleted and the intron is juxtaposed to where the deleted exon 52 would be in a corresponding wild-type dystrophin gene. In some embodiments, the gRNA binds and targets a polynucleotide sequence comprising: (a) a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (b) a fragment of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (c) a complement of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or fragment thereof; (d) a nucleic acid that is substantially identical to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or complement thereof; or (e) a nucleic acid that hybridizes under stringent conditions to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, complement thereof, or a sequence substantially identical thereto. In some embodiments, the gRNA binds and targets or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a variant thereof. In some embodiments, the gRNA spacer comprises a sequence selected from SEQ ID NOs: 29-51, 87, 157-170. In some embodiments, the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 64-86, 88, 171-184. In some embodiments, the gRNA binds or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 35, 40, and 44, or the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 70, 75, and 79. In some embodiments, the donor sequence comprises a polynucleotide sequence selected from SEQ ID NOs: 53-56, 154, and 155. In some embodiments, the donor sequence comprises a polynucleotide of SEQ ID NO: 55. In some embodiments, the donor sequence comprises a polynucleotide of SEQ ID NO: 56. In some embodiments, the Cas protein is a Streptococcus pyogenes Cas9 protein or a Staphylococcus aureus Cas9 protein. In some embodiments, the Cas protein comprises an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 19. In some embodiments, the vector is a viral vector. In some embodiments, the vector is an Adeno-associated virus (AAV) vector. In some embodiments, the AAV vector is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV-10, AAV-11, AAV-12, AAV-13, or AAVrh.74 vector. In some embodiments, one of the one or more vectors comprises a polynucleotide sequence selected from SEQ ID NOs: 57-60 and 129-130. In some embodiments, the molar ratio between gRNA and donor sequence is 1:1, or 1:5, or from 5:1 to 1:10, or from 1:1 to 1:5.

Another aspect of the disclosure provides a recombinant polynucleotide encoding a donor sequence, wherein the donor sequence is flanked on both sides by a gRNA spacer and/or a PAM sequence. In some embodiments, the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of a dystrophin gene. In some embodiments, the dystrophin gene is a human dystrophin gene.

In some embodiments, the system results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween. In some embodiments, the donor sequence comprises a polynucleotide sequence comprising exons 52-79 of the human dystrophin gene. In some embodiments, the donor sequence comprises the polynucleotide sequence of SEQ ID NO: 55 or SEQ ID NO: 56. In some embodiments, the recombinant polynucleotide comprises a sequence selected from SEQ ID NOs: 57-60.

Another aspect of the disclosure provides a vector comprising a recombinant polynucleotide as detailed herein.

Another aspect of the disclosure provides a cell comprising a recombinant polynucleotide of as detailed herein or a vector as detailed herein.

Another aspect of the disclosure provides a composition for restoring dystrophin function in a cell having a mutant dystrophin gene, the composition comprising a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein.

Another aspect of the disclosure provides a kit comprising a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein, or a composition as detailed herein.

Another aspect of the disclosure provides a method for restoring dystrophin function in a cell or a subject having a mutant dystrophin gene. The method may include contacting the cell or the subject with a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein, or a composition as detailed herein. In some embodiments, the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.

Another aspect of the disclosure provides a method for restoring dystrophin function in a cell or a subject having a disrupted dystrophin gene caused by one or more deleted or mutated exons. The method may include contacting the cell or the subject with a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein, or a composition as detailed herein. In some embodiments, the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween. In some embodiments, dystrophin function is restored by inserting one or more wild-type exons of dystrophin gene corresponding to the one or more deleted or mutated exons. In some embodiments, the subject is suffering from Duchenne Muscular Dystrophy.

Another aspect of the disclosure provides a genome editing system for correcting a dystrophin gene. The system may include a donor sequence comprising exons 52-79 or exons 45-79 of the wild-type dystrophin gene. In some embodiments, the genome editing system further includes a nuclease selected from homing endonuclease, zinc finger nuclease, TALEN, and Cas protein.

The disclosure provides for other aspects and embodiments that will be apparent in light of the following detailed description and accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of the dystrophin protein.

FIG. 2 is a schematic diagram of the exons encoding the dystrophin protein and various interactions in the cell.

FIG. 3A, FIG. 3B, FIG. 3C, FIG. 3D, FIG. 3E show that HITI-mediated exon 52 insertion restores full-length dystrophin in humanized hDMDΔ52/mdx primary myofibers. (FIG. 3A) Schematic of dual AAV vector approach for HITI-based exon 52 integration and correction of hDMDΔ52 mutation. Orange pentagon, Cas9/gRNA target sequence. Orange triangle, Cas9 cleavage site with PAM. (FIG. 3B) Primary myoblasts were isolated from hDMDΔ52/mdx skeletal muscle, co-transduced with AAV2 vectors at 1:1 and 1:5 (Cas9:gRNA-donor) vector genome ratios, and differentiated into myofibers. (FIG. 3C) Validation of correct gene knock-in by genomic PCR. (FIG. 3D) Validation of correct donor mRNA splicing by cDNA PCR. (FIG. 3E) Western blot for dystrophin and Cas9 shows restoration of full-length dystrophin expression.

FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, FIG. 4E, FIG. 4F, FIG. 4G, FIG. 4H, FIG. 4I, FIG. 4J show that AAV-CRISPR targeted exon 52 integration restores full-length dystrophin in hDMDΔ52/mdx mouse skeletal muscle. (FIG. 4A) Adult hDMDΔ52/mdx male mice were co-injected in TA muscles with AAV9 vectors at 1:1 and 1:5 (Cas9:gRNA-donor) vector genome ratios. (FIG. 4B) No significant differences in AAV viral genomes per diploid genomes (vg/dg) quantification in TA tissue between corresponding treatment groups. (FIG. 4C) Validation of correct gene knock-in in TA tissue by genomic PCR. Black triangle, detected intact AAV-donor integration. (FIG. 4D) Schematic of potential on-target genomic edits that resulted from targeted DNA cleavage. (FIG. 4E) Unbiased Tn5 tagmentation-based sequencing analysis of the various on-target genomic edits in TA tissues. (FIG. 4F) Unbiased Tn5 tagmentation-based sequencing quantification of total on-target genomic edits in TA tissues. (FIG. 4G) Validation of correct donor mRNA splicing in TA tissue by cDNA PCR. (FIG. 4H) Higher levels of corrected dystrophin transcripts in TA tissue for g7-Ex52 treated mice quantified by ddPCR. (FIG. 4I) Western blot for dystrophin and Cas9 expression shows restoration of dystrophin expression. (FIG. 4J) Dystrophin immunofluorescence staining shows a greater percentage of dystrophin positive fibers in g7-Ex52 treated mice (scale bar, 200 μm; each dot represents mean of 5 images per mouse). One-way ANOVA, followed by Tukey's post hoc multiple comparisons test (**P<0.01 and *P<0.05; mean±SEM; n=4 mice).

FIG. 5A, FIG. 5B, FIG. 5C, FIG. 5D, FIG. 5E, FIG. 5F show that HITI-mediated superexon insertion restores full-length dystrophin in humanized hDMDΔ52/mdx primary myofibers. (FIG. 5A) Schematic of dual AAV vector approach for HITI-based superexon integration and correction of hDMDΔ52 mutation. Pentagon (with black star), Cas9/gRNA target sequence. Triangle, Cas9 cleavage site with PAM. Black hexagon, stop codon. (FIG. 5B) Primary myoblasts were isolated from hDMDΔ52/mdx skeletal muscle, co-transduced with AAV2 vectors at 1:1 and 1:5 (Cas9:gRNA-donor) vector genome ratios, and differentiated into myofibers. (FIG. 5C) Validation of correct gene knock-in by genomic PCR. (FIG. 5D) Validation of correct donor mRNA splicing by cDNA PCR. (FIG. 5E) Characterization of Superexon-corrected polyA tail using 3′ RACE with genome-specific primer (GSP) for 3× stop. (FIG. 5F) Western blot for dystrophin and Cas9 shows restoration of dystrophin expression for Ex52 and superexon treated samples.

FIG. 6A, FIG. 6B, FIG. 6C, FIG. 6D, FIG. 6E, FIG. 6F show that AAV-CRISPR targeted superexon integration restores full-length dystrophin in hDMDΔ52/mdx mouse skeletal muscle. (FIG. 6A) Adult hDMDΔ52/mdx male mice were co-injected in TA muscles with AAV9 vectors at 1:1 and 1:5 (Cas9:gRNA-donor) vector genome ratios. (FIG. 6B) No significant differences in AAV vector genomes per diploid genomes (vg/dg) quantification in TA tissue between corresponding treatment groups. (FIG. 6C) Unbiased Tn5 tagmentation-based sequencing analysis of the various on-target genomic edits in TA tissues. (FIG. 6D) Quantification of corrected dystrophin transcripts in TA tissue by ddPCR. (FIG. 6E) Western blot for dystrophin and Cas9 shows restoration of dystrophin expression. (FIG. 6F) Dystrophin immunofluorescence staining shows a significant increase in the percentage of dystrophin positive fibers in g7-Ex52 treated mice compared to scrambled non-targeted donor control mice (scale bar, 200 μm; each dot represents mean of 5 images per mouse). One-way ANOVA, followed by Tukey's post hoc multiple comparisons test (**P<0.01 and *P<0.05; mean±SEM; n=6 mice).

FIG. 7A, FIG. 78 , FIG. 7C, FIG. 7D, FIG. 7E, FIG. 7F, FIG. 7G, FIG. 7H show that systemic delivery of AAV-CRISPR targeted integration strategies restore full-length dystrophin in hDMDΔ52/mdx mouse cardiac muscle. (FIG. 7A) Systemic facial vein co-injection in P2 neonate hDMDΔ52/mdx male mice with AAV9 vectors at 1:1 and 1:5 (Cas9:gRNA-donor) vector genome ratios. (FIG. 7B) No significant differences in AAV vector genomes per diploid genomes (vg/dg) quantification in cardiac (heart) or skeletal (diaphragm and TA) tissue between corresponding treatment groups. (FIG. 7C) Unbiased Tn5 tagmentation-based sequencing analysis of the various on-target genomic edits shows corrected integration at levels above background in cardiac tissue. (FIG. 7D) Higher levels of corrected dystrophin transcripts in heart tissue for treated mice quantified by ddPCR. (FIG. 7E) Unbiased Tn5 tagmentation-based sequencing analysis of the various on-target heart cDNA shows diverse transcript outcomes including aberrant splicing. (FIG. 7F) Western blot for dystrophin and Cas9 shows restoration of dystrophin expression in heart tissue. (FIG. 7G) Dystrophin immunofluorescence staining in heart tissue shows detection of dystrophin positive fibers in all treated mice, with a significant increase in the percentage of dystrophin positive fibers in g7-superexon (1:1) treated mice compared to scrambled non-targeted donor control mice (scale bar, 200 μm; each dot represents mean of 5 images per mouse). (FIG. 7H) Serum creatine kinase levels show a decrease in hDMDΔ52/mdx treated mice compared to diseased hDMDΔ52/mdx scrambled non-targeted donor control mice. One-way ANOVA, followed by Tukey's post hoc multiple comparisons test (**P<0.01 and *P<0.05; mean t SEM; n=6 mice).

FIG. 8A, FIG. 8B, FIG. 8C, FIG. 8D show gRNA screening and validation of HITI-mediated integration. (FIG. 8A) Schematic of SaCas9 gRNAs targeting within intron 51 upstream of exon52 were designed with 21 nt spacers. (FIG. 8B) Indel formation by individual gRNAs co-transfected with SaCas9 plasmid in HEK293T cells was measured by Surveyor assay, which showed highest editing activity with g3, g6, and g7. (FIG. 8C) Indel formation by individual gRNAs cloned with 19-23nt spacers co-transfected with SaCas9 plasmid in DMD patient myoblasts was measured by Surveyor assay. (FIG. 8D) Electroporation of hDMDΔ52/mdx primary myoblasts with SaCas9 and gRNA AAV plasmids resulted in detection of gene knock-in by PCR and Sanger sequencing.

FIG. 9A, FIG. 9B show unbiased genomic DNA edit characterization of treated hDMDΔ52/mdx TA tissue. (FIG. 9A) Stacked total editing quantification of gDNA editing events in TA tissue from one PBS control and all treated hDMDΔ52/mdx mice using genome-specific primers (GSPs) that prime upstream of the respective gRNA target sites. (FIG. 9B) Editing quantification of corrected, indel, inverted integration, and AAV integration gDNA editing events in TA tissue from one PBS control and all treated hDMDΔ52/mdx mice.

FIG. 10 shows the genome-wide specificity analysis of the g7 gRNA. Identification of the top potential human off-target sites was measured by genome-wide in vitro genomic DNA digestion with g7 and CHANGE-seq analysis. Nucleotides that match the target site are indicated with a dots. Nucleotides that differ from the target are shown for each site. The read count, gRNA sequence (spacer and PAM), and the human genome (hg19) coordinates of the observed on-target and off-target sequences are provided.

FIG. 11A, FIG. 11B show unbiased genomic DNA edit characterization of treated hDMDΔ52/mdx TA tissue. (FIG. 11A) Stacked total editing quantification of gDNA editing events in TA tissue from treated hDMDΔ52/mdx mice. (FIG. 11B) Editing quantification of corrected, indel, inverted integration, and AAV integration gDNA editing events in TA tissue from all treated hDMDΔ52/mdx mice.

FIG. 12A, FIG. 12B show the unbiased genomic DNA edit characterization of treated hDMDΔ52/mdx mice following systemic injection. (FIG. 12A) Stacked total editing quantification of gDNA editing events in heart, diaphragm, and TA tissue from treated hDMDΔ52/mdx mice. (FIG. 12B) Combined editing quantification of corrected, indel, inverted integration, and AAV integration gDNA editing events in heart, diaphragm, and TA tissue from all treated hDMDΔ52/mdx mice.

FIG. 13A, FIG. 13B show the unbiased transcript edit characterization of treated hDMDΔ52/mdx cardiac tissue. (FIG. 13A) Quantification of transcript editing events in cardiac tissue from one non-targeted donor control and all treated hDMDΔ52/mdx mice. (FIG. 13B) Schematic of frequent SaCas9-containing transcript reads demonstrating on-target aberrant splicing with AAV-SaCas9 construct sequences and confirmed with corresponding cardiac genomic reads containing aligned Cas9-coding sequences.

FIG. 14 shows the nested quantification and representative immunofluorescence staining for full-length dystrophin restoration in cardiac tissue. For all dystrophin positive fiber quantification, 5 randomized images were taken for each mouse sample and human dystrophin-positive and total fibers (anti-laminin) were counted. A representative image of cardiac tissue is provided for each treated mouse. Nested quantification values were used for statistical analysis (scale bar, 200 μm; each dot represents mean a single quantification per mouse). One-way ANOVA, followed by Tukey's post hoc multiple comparisons test (*P<0.05; mean±SEM; n=6 mice).

DETAILED DESCRIPTION

Described herein are CRISPR/Cas-based gene/genome editing compositions and methods for treating Duchenne Muscular Dystrophy (DMD) by restoring dystrophin function. DMD is typically caused by deletions in the dystrophin gene that disrupt the reading frame. Many strategies to treat DMD aim to restore the reading frame by removing or skipping over an additional exon, as it has been shown that an internally truncated dystrophin protein can still be partially functional. Detailed herein are AAV-based Homology-Independent Targeted Integration (HITI)-mediated gene editing therapies for correcting the dystrophin gene. Specifically, the CRISPR/Cas9 gene editing technology was adapted to direct the targeted insertion of missing exons into the dystrophin gene. As a therapeutically relevant target, HITI-mediated genome editing strategies were optimized in a humanized mouse model of DMD in which exon 52 has been removed in mice carrying the full-length human dystrophin gene (hDMDΔ52/mdx mice). To achieve targeted integration, an AAV vector containing the deleted genome sequence including exon 52, or in some cases exons 52-79, or in some cases exons 45-79, is co-delivered with an AAV vector encoding Cas9/gRNA expression cassettes to achieve full-length dystrophin restoration in skeletal and cardiac muscles. The AAV delivery system is used to express Cas9 and gRNAs to generate a targeted genomic DSB and to deliver donor templates for NHEJ-mediated integration at the cut site. Targeted integration of the exon(s) in cultured cells is confirmed. Combined with AAV delivery, HITI-mediated strategies for targeted insertion of missing exons provides a method to restore full-length dystrophin and improve functional outcomes.

1. DEFINITIONS

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and,” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

The term “about” or “approximately” as used herein as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In certain aspects, the term “about” refers to a range of values that fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Alternatively, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

“Adeno-associated virus” or “AAV” as used interchangeably herein refers to a small virus belonging to the genus Dependovirus of the Parvoviridae family that infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response.

“Amino acid” as used herein refers to naturally occurring and non-natural synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code. Amino acids can be referred to herein by either their commonly known three-letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Amino acids include the side chain and polypeptide backbone portions.

“Binding region” as used herein refers to the region within a target region that is recognized and bound by the CRISPR/Cas-based gene editing system.

“Clustered Regularly Interspaced Short Palindromic Repeats” and “CRISPRs”, as used interchangeably herein, refers to loci containing multiple short direct repeats that are found in the genomes of approximately 40% of sequenced bacteria and 90% of sequenced archaea.

“Coding sequence” or “encoding nucleic acid” as used herein means the nucleic acids (RNA or DNA molecule) that comprise a nucleotide sequence which encodes a protein. The coding sequence can further include initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of an individual or mammal to which the nucleic acid is administered. The coding sequence may be codon optimized.

“Complement” or “complementary” as used herein means a nucleic acid can mean Watson-Crick (e.g., A-T/U and C-G) or Hoogsteen base pairing between nucleotides or nucleotide analogs of nucleic acid molecules. “Complementarity” refers to a property shared between two nucleic acid sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position will be complementary.

The terms “control,” “reference level,” and “reference” are used herein interchangeably. The reference level may be a predetermined value or range, which is employed as a benchmark against which to assess the measured result. “Control group” as used herein refers to a group of control subjects. The predetermined level may be a cutoff value from a control group. The predetermined level may be an average from a control group. Cutoff values (or predetermined cutoff values) may be determined by Adaptive Index Model (AIM) methodology. Cutoff values (or predetermined cutoff values) may be determined by a receiver operating curve (ROC) analysis from biological samples of the patient group. ROC analysis, as generally known in the biological arts, is a determination of the ability of a test to discriminate one condition from another, e.g., to determine the performance of each marker in identifying a patient having CRC. A description of ROC analysis is provided in P. J. Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of which is hereby incorporated by reference in its entirety. Alternatively, cutoff values may be determined by a quartile analysis of biological samples of a patient group. For example, a cutoff value may be determined by selecting a value that corresponds to any value in the 25th-75th percentile range, preferably a value that corresponds to the 25th percentile, the 50th percentile or the 75th percentile, and more preferably the 75th percentile. Such statistical analyses may be performed using any method known in the art and can be implemented through any number of commercially available software packages (e.g., from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station, Tex.; SAS Institute Inc., Cary, N.C.). The healthy or normal levels or ranges for a target or for a protein activity may be defined in accordance with standard practice. A control may be a subject or cell without a composition as detailed herein. A control may be a subject, or a sample therefrom, whose disease state is known. The subject, or sample therefrom, may be healthy, diseased, diseased prior to treatment, diseased during treatment, or diseased after treatment, or a combination thereof.

“Correcting”, “gene editing,” and “restoring” as used herein refers to changing a mutant gene that encodes a dysfunctional protein or truncated protein or no protein at all, such that a full-length functional or partially full-length functional protein expression is obtained. Correcting or restoring a mutant gene may include replacing the region of the gene that has the mutation or replacing the entire mutant gene with a copy of the gene that does not have the mutation with a repair mechanism such as homology-directed repair (HDR). Correcting or restoring a mutant gene may also include repairing a frameshift mutation that causes a premature stop codon, an aberrant splice acceptor site or an aberrant splice donor site, by generating a double stranded break in the gene that is then repaired using non-homologous end joining (NHEJ). NHEJ may add or delete at least one base pair during repair which may restore the proper reading frame and eliminate the premature stop codon. Correcting or restoring a mutant gene may also include disrupting an aberrant splice acceptor site or splice donor sequence. Correcting or restoring a mutant gene may also include deleting a non-essential gene segment by the simultaneous action of two nucleases on the same DNA strand in order to restore the proper reading frame by removing the DNA between the two nuclease target sites and repairing the DNA break by NHEJ.

“Donor DNA”, “donor template,” and “repair template” as used interchangeably herein refers to a double-stranded DNA fragment or molecule that includes at least a portion of the gene of interest. The donor DNA may encode a full-functional protein or a partially functional protein.

“Duchenne Muscular Dystrophy” or “DMD” as used interchangeably herein refers to a recessive, fatal, X-linked disorder that results in muscle degeneration and eventual death. DMD is a common hereditary monogenic disease and occurs in 1 in 3500 males. DMD is the result of inherited or spontaneous mutations that cause nonsense or frame shift mutations in the dystrophin gene. The majority of dystrophin mutations that cause DMD are deletions of exons that disrupt the reading frame and cause premature translation termination in the dystrophin gene. DMD patients typically lose the ability to physically support themselves during childhood, become progressively weaker during the teenage years, and die in their twenties.

“Dystrophin” as used herein refers to a rod-shaped cytoplasmic protein which is a part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Dystrophin provides structural stability to the dystroglycan complex of the cell membrane that is responsible for regulating muscle cell integrity and function. The dystrophin gene or “DMD gene” as used interchangeably herein is 2.2 megabases at locus Xp21. The primary transcription measures about 2,400 kb with the mature mRNA being about 14 kb. 79 exons code for the protein which is over 3500 amino acids.

“Enhancer” as used herein refers to non-coding DNA sequences containing multiple activator and repressor binding sites. Enhancers range from 200 bp to 1 kb in length and may be either proximal, 5′ upstream to the promoter or within the first intron of the regulated gene, or distal, in introns of neighboring genes or intergenic regions far away from the locus. Through DNA looping, active enhancers contact the promoter dependently of the core DNA binding motif promoter specificity. 4 to 5 enhancers may interact with a promoter. Similarly, enhancers may regulate more than one gene without linkage restriction and may “skip” neighboring genes to regulate more distant ones. Transcriptional regulation may involve elements located in a chromosome different to one where the promoter resides. Proximal enhancers or promoters of neighboring genes may serve as platforms to recruit more distal elements.

“Frameshift” or “frameshift mutation” as used interchangeably herein refers to a type of gene mutation wherein the addition or deletion of one or more nucleotides causes a shift in the reading frame of the codons in the mRNA. The shift in reading frame may lead to the alteration in the amino acid sequence at protein translation, such as a missense mutation or a premature stop codon.

“Functional” and “full-functional” as used herein describes protein that has biological activity. A “functional gene” refers to a gene transcribed to mRNA, which is translated to a functional protein.

“Fusion protein” as used herein refers to a chimeric protein created through the joining of two or more genes that originally coded for separate proteins. The translation of the fusion gene results in a single polypeptide with functional properties derived from each of the original proteins.

“Homology-directed repair” or “HDR” as used interchangeably herein refers to a mechanism in cells to repair double strand DNA lesions when a homologous piece of DNA is present in the nucleus, mostly in G2 and S phase of the cell cycle. HDR uses a donor DNA template to guide repair and may be used to create specific sequence changes to the genome, including the targeted addition of whole genes. If a donor template is provided along with the CRISPR/Cas9-based gene editing system, then the cellular machinery will repair the break by homologous recombination, which is enhanced several orders of magnitude in the presence of DNA cleavage. When the homologous DNA piece is absent, non-homologous end joining may take place instead.

“Genetic construct” as used herein refers to the DNA or RNA molecules that comprise a polynucleotide that encodes a protein. The coding sequence includes initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of the individual to whom the nucleic acid molecule is administered. As used herein, the term “expressible form” refers to gene constructs that contain the necessary regulatory elements operable linked to a coding sequence that encodes a protein such that when present in the cell of the individual, the coding sequence will be expressed.

“Genome editing” or “gene editing” as used herein refers to changing a gene. Genome editing may include correcting or restoring a mutant gene or adding additional mutations. Genome editing may include knocking out a gene, such as a mutant gene or a normal gene. Genome editing may be used to treat disease or, for example, enhance muscle repair, by changing the gene of interest. In some embodiments, the compositions and methods detailed herein are for use in somatic cells and not germ line cells.

The term “heterologous” as used herein refers to nucleic acid comprising two or more subsequences that are not found in the same relationship to each other in nature. For instance, a nucleic acid that is recombinantly produced typically has two or more sequences from unrelated genes synthetically arranged to make a new functional nucleic acid, for example, a promoter from one source and a coding region from another source. The two nucleic acids are thus heterologous to each other in this context. When added to a cell, the recombinant nucleic acids would also be heterologous to the endogenous genes of the cell. Thus, in a chromosome, a heterologous nucleic acid would include a non-native (non-naturally occurring) nucleic acid that has integrated into the chromosome, or a non-native (non-naturally occurring) extrachromosomal nucleic acid. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (for example, a “fusion protein,” where the two subsequences are encoded by a single nucleic acid sequence).

“Identical” or “identity” as used herein in the context of two or more polynucleotide or polypeptide sequences means that the sequences have a specified percentage of residues that are the same over a specified region. The percentage may be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity. In cases where the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of single sequence are included in the denominator but not the numerator of the calculation. When comparing DNA and RNA, thymine (T) and uracil (U) may be considered equivalent. Identity may be performed manually or by using a computer sequence algorithm such as BLAST or BLAST 2.0.

“Mutant gene” or “mutated gene” as used interchangeably herein refers to a gene that has undergone a detectable mutation. A mutant gene has undergone a change, such as the loss, gain, or exchange of genetic material, which affects the normal transmission and expression of the gene. A “disrupted gene” as used herein refers to a mutant gene that has a mutation that causes a premature stop codon. The disrupted gene product is truncated relative to a full-length undisrupted gene product.

“Non-homologous end joining (NHEJ) pathway” as used herein refers to a pathway that repairs double-strand breaks in DNA by directly ligating the break ends without the need for a homologous template. The template-independent re-ligation of DNA ends by NHEJ is a stochastic, error-prone repair process that introduces random micro-insertions and micro-deletions (indels) at the DNA breakpoint. This method may be used to intentionally disrupt, delete, or alter the reading frame of targeted gene sequences. NHEJ typically uses short homologous DNA sequences called microhomologies to guide repair. These microhomologies are often present in single-stranded overhangs on the end of double-strand breaks. When the overhangs are perfectly compatible, NHEJ usually repairs the break accurately, yet imprecise repair leading to loss of nucleotides may also occur, but is much more common when the overhangs are not compatible.

“Normal gene” as used herein refers to a gene that has not undergone a change, such as a loss, gain, or exchange of genetic material. The normal gene undergoes normal gene transmission and gene expression. For example, a normal gene may be a wild-type gene.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” as used herein means at least two nucleotides covalently linked together. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a polynucleotide also encompasses the complementary strand of a depicted single strand. Many variants of a polynucleotide may be used for the same purpose as a given polynucleotide. Thus, a polynucleotide also encompasses substantially identical polynucleotides and complements thereof. A single strand provides a probe that may hybridize to a target sequence under stringent hybridization conditions. Thus, a polynucleotide also encompasses a probe that hybridizes under stringent hybridization conditions. Polynucleotides may be single stranded or double stranded or may contain portions of both double stranded and single stranded sequence. The polynucleotide can be nucleic acid, natural or synthetic, DNA, genomic DNA, cDNA, RNA, or a hybrid, where the polynucleotide can contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including, for example, uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine, and isoguanine. Polynucleotides can be obtained by chemical synthesis methods or by recombinant methods.

“Open reading frame” refers to a stretch of codons that begins with a start codon and ends at a stop codon. In eukaryotic genes with multiple exons, introns are removed, and exons are then joined together after transcription to yield the final mRNA for protein translation. An open reading frame may be a continuous stretch of codons. In some embodiments, the open reading frame only applies to spliced mRNAs, not genomic DNA, for expression of a protein.

“Operably linked” as used herein means that expression of a gene is under the control of a promoter with which it is spatially connected. A promoter may be positioned 5′ (upstream) or 3′ (downstream) of a gene under its control. The distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function. Nucleic acid or amino acid sequences are “operably linked” (or “operatively linked”) when placed into a functional relationship with one another. For instance, a promoter or enhancer is operably linked to a coding sequence if it regulates, or contributes to the modulation of, the transcription of the coding sequence. Operably linked DNA sequences are typically contiguous, and operably linked amino acid sequences are typically contiguous and in the same reading frame. However, since enhancers generally function when separated from the promoter by up to several kilobases or more and intronic sequences may be of variable lengths, some polynucleotide elements may be operably linked but not contiguous. Similarly, certain amino acid sequences that are non-contiguous in a primary polypeptide sequence may nonetheless be operably linked due to, for example folding of a polypeptide chain. With respect to fusion polypeptides, the terms “operatively linked” and “operably linked” can refer to the fact that each of the components performs the same function in linkage to the other component as it would if it were not so linked.

“Partially-functional” as used herein describes a protein that is encoded by a mutant gene and has less biological activity than a functional protein but more than a non-functional protein.

A “peptide” or “polypeptide” is a linked sequence of two or more amino acids linked by peptide bonds. The polypeptide can be natural, synthetic, or a modification or combination of natural and synthetic. Peptides and polypeptides include proteins such as binding proteins, receptors, and antibodies. The terms “polypeptide”, “protein,” and “peptide” are used interchangeably herein. “Primary structure” refers to the amino acid sequence of a particular peptide. “Secondary structure” refers to locally ordered, three dimensional structures within a polypeptide. These structures are commonly known as domains, for example, enzymatic domains, extracellular domains, transmembrane domains, pore domains, and cytoplasmic tail domains. “Domains” are portions of a polypeptide that form a compact unit of the polypeptide and are typically 15 to 350 amino acids long. Exemplary domains include domains with enzymatic activity or ligand binding activity. Typical domains are made up of sections of lesser organization such as stretches of beta-sheet and alpha-helices. “Tertiary structure” refers to the complete three-dimensional structure of a polypeptide monomer. “Quaternary structure” refers to the three-dimensional structure formed by the noncovalent association of independent tertiary units. A “motif” is a portion of a polypeptide sequence and includes at least two amino acids. A motif may be 2 to 20, 2 to 15, or 2 to 10 amino acids in length. In some embodiments, a motif includes 3, 4, 5, 6, or 7 sequential amino acids. A domain may be comprised of a series of the same type of motif.

“Premature stop codon” or “out-of-frame stop codon” as used interchangeably herein refers to nonsense mutation in a sequence of DNA, which results in a stop codon at location not normally found in the wild-type gene. A premature stop codon may cause a protein to be truncated or shorter compared to the full-length version of the protein.

“Promoter” as used herein means a synthetic or naturally derived molecule which is capable of conferring, activating or enhancing expression of a nucleic acid in a cell. A promoter may comprise one or more specific transcriptional regulatory sequences to further enhance expression and/or to alter the spatial expression and/or temporal expression of same. A promoter may also comprise distal enhancer or repressor elements, which may be located as much as several thousand base pairs from the start site of transcription. A promoter may be derived from sources including viral, bacterial, fungal, plants, insects, and animals. A promoter may regulate the expression of a gene component constitutively, or differentially with respect to cell, the tissue or organ in which expression occurs or, with respect to the developmental stage at which expression occurs, or in response to external stimuli such as physiological stresses, pathogens, metal ions, or inducing agents. Representative examples of promoters include the bacteriophage T7 promoter, bacteriophage T3 promoter, SP6 promoter, lac operator-promoter, tac promoter, SV40 late promoter, SV40 early promoter, RSV-LTR promoter, CMV IE promoter, SV40 early promoter or SV40 late promoter, human U6 (hU6) promoter, and CMV IE promoter. Promoters that target muscle-specific stem cells may include, for example, the CK8 promoter, the Spc5-12 promoter, and the MHCK7 promoter.

The term “recombinant” when used with reference to, for example, a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein, or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (naturally occurring) form of the cell or express a second copy of a native gene that is otherwise normally or abnormally expressed, under expressed, or not expressed at all.

“Sample” or “test sample” as used herein can mean any sample in which the presence and/or level of a target is to be detected or determined or any sample comprising a DNA targeting or gene editing system or component thereof as detailed herein. Samples may include liquids, solutions, emulsions, or suspensions. Samples may include a medical sample. Samples may include any biological fluid or tissue, such as blood, whole blood, fractions of blood such as plasma and serum, muscle, interstitial fluid, sweat, saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid, nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid, gastric lavage, emesis, fecal matter, lung tissue, peripheral blood mononuclear cells, total white blood cells, lymph node cells, spleen cells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid, skin, or combinations thereof. In some embodiments, the sample comprises an aliquot. In other embodiments, the sample comprises a biological fluid. Samples can be obtained by any means known in the art. The sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art.

“Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal that wants or is in need of the herein described compositions or methods. The subject may be a human or a non-human. The subject may be a vertebrate. The subject may be a mammal. The mammal may be a primate or a non-primate. The mammal can be a non-primate such as, for example, cow, pig, camel, llama, hedgehog, anteater, platypus, elephant, alpaca, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse. The mammal can be a primate such as a human. The mammal can be a non-human primate such as, for example, monkey, cynomolgous monkey, rhesus monkey, chimpanzee, gorilla, orangutan, and gibbon. The subject may be of any age or stage of development, such as, for example, an adult, an adolescent, or an infant. The subject may be male. The subject may be female. In some embodiments, the subject has a specific genetic marker. The subject may be undergoing other forms of treatment.

“Substantially identical” can mean that a first and second amino acid or polynucleotide sequence are at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% over a region of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 amino acids or nucleotides, respectively.

“Target gene” as used herein refers to any nucleotide sequence encoding a known or putative gene product. The target gene may be a mutated gene involved in a genetic disease. The target gene may encode a known or putative gene product that is intended to be corrected or for which its expression is intended to be modulated. In certain embodiments, the target gene is the dystrophin gene or a portion thereof.

“Target region” as used herein refers to the region of the target gene to which the CRISPR/Cas9-based gene editing or targeting system is designed to bind.

“Transgene” as used herein refers to a gene or genetic material containing a gene sequence that has been isolated from one organism and is introduced into a different organism. This non-native segment of DNA may retain the ability to produce RNA or protein in the transgenic organism, or it may alter the normal function of the transgenic organism's genetic code. The introduction of a transgene has the potential to change the phenotype of an organism.

Transcriptional regulatory elements” or “regulatory elements” refers to a genetic element which can control the expression of nucleic acid sequences, such as activate, enhancer, or decrease expression, or alter the spatial and/or temporal expression of a nucleic acid sequence. Examples of regulatory elements include, for example, promoters, enhancers, splicing signals, polyadenylation signals, and termination signals. A regulatory element can be “endogenous,” “exogenous,” or “heterologous” with respect to the gene to which it is operably linked. An “endogenous” regulatory element is one which is naturally linked with a given gene in the genome. An “exogenous” or “heterologous” regulatory element is one which is not normally linked with a given gene but is placed in operable linkage with a gene by genetic manipulation.

“Treatment” or “treating” or “treatment” when referring to protection of a subject from a disease, means suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of disease, or completely eliminating a disease. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Preventing the disease involves administering a composition of the present invention to a subject prior to onset of the disease. Suppressing the disease involves administering a composition of the present invention to a subject after induction of the disease but before its clinical appearance. Repressing or ameliorating the disease involves administering a composition of the present invention to a subject after clinical appearance of the disease. As used herein, the term “gene therapy” refers to a method of treating a patient wherein polypeptides or nucleic acid sequences are transferred into cells of a patient such that activity and/or the expression of a particular gene is modulated. In certain embodiments, the expression of the gene is suppressed. In certain embodiments, the expression of the gene is enhanced. In certain embodiments, the temporal or spatial pattern of the expression of the gene is modulated.

“Variant” used herein with respect to a polynucleotide means (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequences substantially identical thereto.

“Variant” with respect to a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity. Variant may also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity. Representative examples of “biological activity” include the ability to be bound by a specific antibody or polypeptide or to promote an immune response. Variant can mean a functional fragment thereof. Variant can also mean multiple copies of a polypeptide. The multiple copies can be in tandem or separated by a linker. A conservative substitution of an amino acid, for example, replacing an amino acid with a different amino acid of similar properties (for example, hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes may be identified, in part, by considering the hydropathic index of amino acids, as understood in the art (Kyte et al., J. Mol. Biol. 1982, 157, 105-132). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes may be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids may also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide. Substitutions may be performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.

“Vector” as used herein means a nucleic acid sequence containing an origin of replication. A vector may be a viral vector, bacteriophage, bacterial artificial chromosome, or yeast artificial chromosome. A vector may be a DNA or RNA vector. A vector may be a self-replicating extrachromosomal vector, and preferably, is a DNA plasmid. For example, the vector may encode a Cas9 protein and at least one gRNA molecule.

Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

2. DYSTROPHIN

Dystrophin is a rod-shaped cytoplasmic protein and a part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane (FIG. 1 ). Dystrophin provides structural stability to the dystroglycan complex of the cell membrane. The dystrophin gene is 2.2 megabases at locus Xp21. The primary transcription measures about 2,400 kb with the mature mRNA being about 14 kb. 79 exons include approximately 2.2 million nucleotides and code for the protein, which is over 3500 amino acids (FIG. 2 ). The large size of the dystrophin gene as well as its repetitive elements make the gene susceptible to recombination, leading to deletions of one or more exons. Normal skeleton muscle tissue contains only small amounts of dystrophin, but its absence of abnormal expression leads to the development of severe and incurable symptoms. Some mutations in the dystrophin gene lead to the production of defective dystrophin and severe dystrophic phenotype in affected patients. Some mutations in the dystrophin gene lead to partially-functional dystrophin protein and a much milder dystrophic phenotype in affected patients.

DMD is the result of inherited or spontaneous mutations that cause nonsense or frame shift mutations in the dystrophin gene. DMD is the most prevalent lethal heritable childhood disease and affects approximately one in 5,000 newborn males. DMD is characterized by progressive muscle weakness, often leading to mortality in subjects at age mid-twenties, due to the lack of a functional dystrophin gene. Most mutations are deletions in the dystrophin gene that disrupt the reading frame. Naturally occurring mutations and their consequences are relatively well understood for DMD. In-frame deletions that occur in the exon 45-55 regions contained within the rod domain can produce highly functional dystrophin proteins, and many carriers are asymptomatic or display mild symptoms. Exons 45-55 of dystrophin are a mutational hotspot. Furthermore, more than 60% of patients may be treated by targeting exons in this region of the dystrophin gene. Efforts have been made to restore the disrupted dystrophin reading frame in DMD patients by skipping non-essential exon(s) (for example, exon 45 skipping) during mRNA splicing to produce internally deleted but functional dystrophin proteins. One therapeutic aim may be to generate expression of a truncated, but partially functional, dystrophin protein that is similar to the product of the DMD gene in Becker muscular dystrophy (BMD) that is associated with milder symptoms relative to DMD. The deletion of internal dystrophin exon(s) (for example, deletion of exon 45) may retain the proper reading frame and can generate an internally truncated but partially functional dystrophin protein. Deletions between exons 45-55 of dystrophin can result in a phenotype that is much milder compared to DMD.

A dystrophin gene may be a mutant dystrophin gene. A dystrophin gene may be a wild-type dystrophin gene. A dystrophin gene may have a sequence that is functionally identical to a wild-type dystrophin gene, for example, the sequence may be codon-optimized but still encode for the same protein as the wild-type dystrophin. A mutant dystrophin gene may include one or more mutations relative to the wild-type dystrophin gene. Mutations may include, for example, nucleotide deletions, substitutions, additions, transversions, or combinations thereof. Mutations may be in one or more exons and/or introns. Mutations may include deletions of all or parts of at least one intron and/or exon. An exon of a mutant dystrophin gene may be mutated or at least partially deleted from the dystrophin gene. An exon of a mutant dystrophin gene may be fully deleted. A mutant dystrophin gene may have a portion or fragment thereof that corresponds to the corresponding sequence in the wild-type dystrophin gene. In some embodiments, a disrupted dystrophin gene caused by a deleted or mutated exon can be restored in DMD patients by adding back the corresponding wild-type exon. In some embodiments, disrupted dystrophin caused by, for example, a deleted or mutated exon 52, can be restored in DMD patients by adding back in wild-type exon 52. In certain embodiments, exon 52 of a dystrophin gene refers to the 52nd exon of the dystrophin gene. Exon 52 is frequently adjacent to frame-disrupting deletions in DMD patients. Addition of exon 52 to restore the reading frame may ameliorate the phenotype in DMD subjects, including DMD subjects with deletion mutations. In certain embodiments, one or more exons may be added and inserted into the disrupted dystrophin gene. The one or more exons may be added and inserted so as to restore the corresponding mutated or deleted exon(s) in dystrophin. The one or more exons may be added and inserted into the disrupted dystrophin gene in addition to adding back and inserting the exon 52. In some embodiments, the one or more exons added and inserted into the disrupted dystrophin gene include exons 52-79. In some embodiments, the one or more exons added and inserted into the disrupted dystrophin gene include exons 45-79.

3. CRISPR/CAS9-BASED GENE EDITING SYSTEM

The compositions and methods detailed herein may be suitable for any gene editing system or tool wherein two targeting nucleases are combined to create a deletion in a genome. Gene editing systems may include, for example, those comprising homing endonucleases, zinc finger nucleases (ZFNs), transcription activator-like effector (TALE) nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas protein) such as Cas9. Homing endonucleases generally cleave their DNA substrates as dimers and do not have distinct binding and cleavage domains. ZFNs recognize target sites that consist of two zinc-finger binding sites that flank a 5- to 7-base pair (bp) spacer sequence recognized by the FokI cleavage domain. TALENs recognize target sites that consist of two TALE DNA-binding sites that flank a 12- to 20-bp spacer sequence recognized by the FokI cleavage domain. In some embodiments, the compositions and methods detailed herein may be used with CRISPR/Cas9-based gene editing systems. Provided herein are CRISPR/Cas9-based gene editing systems. The CRISPR/Cas9-based gene editing system may be used to restore dystrophin gene function. The CRISPR/Cas9-based gene editing system may include a Cas9 protein or a fusion protein, and at least one gRNA.

“Clustered Regularly Interspaced Short Palindromic Repeats” and “CRISPRs,” as used interchangeably herein, refers to loci containing multiple short direct repeats that are found in the genomes of approximately 40% of sequenced bacteria and 90% of sequenced archaea. The CRISPR system is a microbial nuclease system involved in defense against invading phages and plasmids that provides a form of acquired immunity. The CRISPR loci in microbial hosts contain a combination of CRISPR-associated (Cas) genes as well as non-coding RNA elements capable of programming the specificity of the CRISPR-mediated nucleic acid cleavage. Short segments of foreign DNA, called spacers, are incorporated into the genome between CRISPR repeats, and serve as a “memory” of past exposures. Cas9 forms a complex with the 3′ end of a sgRNA (which may be referred interchangeably herein as “gRNA”), and the protein-RNA pair recognizes its genomic target by complementary base pairing between the 5′ end of the sgRNA sequence and a predefined 20 bp DNA sequence, known as the protospacer. This complex is directed to homologous loci of pathogen DNA via regions encoded within the crRNA, i.e., the protospacers, and protospacer-adjacent motifs (PAMs) within the pathogen genome. The non-coding CRISPR array is transcribed and cleaved within direct repeats into short crRNAs containing individual spacer sequences, which direct Cas nucleases to the target site (protospacer). By simply exchanging the 20 bp recognition sequence of the expressed sgRNA, the Cas9 nuclease can be directed to new genomic targets. CRISPR spacers are used to recognize and silence exogenous genetic elements in a manner analogous to RNAi in eukaryotic organisms.

Three classes of CRISPR systems (Types I, II, and III effector systems) are known. The Type II effector system carries out targeted DNA double-strand break in four sequential steps, using a single effector enzyme, Cas9, to cleave dsDNA. Compared to the Type I and Type III effector systems, which require multiple distinct effectors acting as a complex, the Type II effector system may function in alternative contexts such as eukaryotic cells. The Type II effector system consists of a long pre-crRNA, which is transcribed from the spacer-containing CRISPR locus, the Cas9 protein, and a tracrRNA, which is involved in pre-crRNA processing. The tracrRNAs hybridize to the repeat regions separating the spacers of the pre-crRNA, thus initiating dsRNA cleavage by endogenous RNase Ill. This cleavage is followed by a second cleavage event within each spacer by Cas9, producing mature crRNAs that remain associated with the tracrRNA and Cas9, forming a Cas9:crRNA-tracrRNA complex.

The Cas9:crRNA-tracrRNA complex unwinds the DNA duplex and searches for sequences matching the crRNA to cleave. Target recognition occurs upon detection of complementarity between a “protospacer” sequence in the target DNA and the remaining spacer sequence in the crRNA. Cas9 mediates cleavage of target DNA if a correct protospacer-adjacent motif (PAM) is also present at the 3′ end of the protospacer. For protospacer targeting, the sequence must be immediately followed by the protospacer-adjacent motif (PAM), a short sequence recognized by the Cas9 nuclease that is required for DNA cleavage. Different Type II systems have differing PAM requirements.

An engineered form of the Type II effector system of S. pyogenes was shown to function in human cells for genome engineering. In this system, the Cas9 protein was directed to genomic target sites by a synthetically reconstituted “guide RNA” (“gRNA”, also used interchangeably herein as a chimeric single guide RNA (“sgRNA”)), which is a crRNA-tracrRNA fusion that obviates the need for RNase III and crRNA processing in general. Provided herein are CRISPR/Cas9-based engineered systems for use in gene editing and treating genetic diseases. The CRISPR/Cas9-based engineered systems can be designed to target any gene, including genes involved in, for example, a genetic disease, aging, tissue regeneration, or wound healing. The CRISPR/Cas9-based gene editing system can include a Cas9 protein or a Cas9 fusion protein.

a. Cas9 Protein

Cas9 protein is an endonuclease that cleaves nucleic acid and is encoded by the CRISPR loci and is involved in the Type II CRISPR system. The Cas9 protein can be from any bacterial or archaea species, including, but not limited to, Streptococcus pyogenes, Staphylococcus aureus (S. aureus), Acidovorax avenae, Actinobacillus pleuropneumoniae, Actinobacillus succinogenes, Actinobacillus suis, Actinomyces sp., cycliphilus denitrificans, Aminomonas paucivorans, Bacillus cereus, Bacillus smithii, Bacillus thuringiensis, Bacteroides sp., Blastopirellula manina, Bradyrhizobium sp., Brevibacillus laterosporus, Campylobacter coli, Campylobacter jejuni, Campylobacter lari, candidatus punicei spirillum, Clostridium cellulolyticum, Clostridium perfringens, Corynebacterium accolens, Corynebacterium diphtheria, Corynebacterium matruchotii, Dinoroseobacter shibae, Eubacterium dolichum, gamma proteobacterium, Gluconacetobacter diazotrophicus, Haemophilus parainfluenzae, Haemophilus sputorum, Helicobacter canadensis, Helicobacter cinaedi, Helicobacter mustelae, Ilyobacter polytropus, Kingella kingae, Lactobacillus crispatus, Listeria ivanovii, Listeria monocytogenes, Listeriaceae bacterium, Methylocystis sp., Methylosinus trichosporium, Mobiluncus mulieris, Neisseria bacilliformis, Neisseria cinerea, Neisseria flavescens, Neisseria lactamica, Neisseria sp., Neisseria wadsworthii, Nitrosomonas sp., Parvibaculum lavamentivorans, Pasteurella multocida, Phascolarctobacterium succinatutens, Ralstonia syzygii, Rhodopseudomonas palustris, Rhodovulum sp., Simonsiella muelleri, Sphingomonas sp., Sporolactobacillus vineae, Staphylococcus lugdunensis, Streptococcus sp., Subdoligranulum sp., Tistrella mobilis, Treponema sp., or Verminephrobacter eiseniae. In certain embodiments, the Cas9 molecule is a Streptococcus pyogenes Cas9 molecule (also referred herein as “SpCas9”). SpCas9 may comprise an amino acid sequence of SEQ ID NO: 18. In certain embodiments, the Cas9 molecule is a Staphylococcus aureus Cas9 molecule (also referred herein as “SaCas9”). SaCas9 may comprise an amino acid sequence of SEQ ID NO: 19.

A Cas9 molecule or a Cas9 fusion protein can interact with one or more gRNA molecule(s) and, in concert with the gRNA molecule(s), can localize to a site that comprises a target domain, and in certain embodiments, a PAM sequence. The Cas9 protein forms a complex with the 3′ end of a gRNA. The ability of a Cas9 molecule or a Cas9 fusion protein to recognize a PAM sequence can be determined, for example, by using a transformation assay as known in the art.

The specificity of the CRISPR-based system may depend on two factors: the target sequence and the protospacer-adjacent motif (PAM). The targeting sequence is located on the 5′ end of the gRNA and is designed to bond with base pairs on the host DNA at the correct DNA sequence known as the protospacer or target sequence. By simply exchanging the recognition sequence of the gRNA, the Cas9 protein can be directed to new genomic targets. The PAM sequence is located on the DNA to be altered and is recognized by a Cas9 protein. PAM recognition sequences of the Cas9 protein can be species specific.

In certain embodiments, the ability of a Cas9 molecule or a Cas9 fusion protein to interact with and cleave a target nucleic acid is PAM sequence dependent. A PAM sequence is a sequence in the target nucleic acid. In certain embodiments, cleavage of the target nucleic acid occurs upstream from the PAM sequence. Cas9 molecules from different bacterial species can recognize different sequence motifs (for example, PAM sequences). A Cas9 molecule of S. pyogenes may recognize the PAM sequence of NRG (5′-NRG-3′, where R is any nucleotide residue, and in some embodiments, R is either A or G, SEQ ID NO: 1). In certain embodiments, a Cas9 molecule of S. pyogenes may naturally prefer and recognize the sequence motif NGG (SEQ ID NO: 2) and direct cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from that sequence. In some embodiments, a Cas9 molecule of S. pyogenes accepts other PAM sequences, such as NAG (SEQ ID NO: 3) in engineered systems (Hsu et al., Nature Biotechnology 2013 doi:10.1038/nbt.2647). In certain embodiments, a Cas9 molecule of S. thermophilus recognizes the sequence motif NGGNG (SEQ ID NO: 4) and/or NNAGAAW (W=A or T) (SEQ ID NO: 5) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from these sequences. In certain embodiments, a Cas9 molecule of S. mutans recognizes the sequence motif NGG (SEQ ID NO: 2) and/or NAAR (R=A or G) (SEQ ID NO: 6) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5 bp, upstream from this sequence. In certain embodiments, a Cas9 molecule of S. aureus recognizes the sequence motif NNGRR (R=A or G) (SEQ ID NO: 7) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from that sequence. In certain embodiments, a Cas9 molecule of S. aureus recognizes the sequence motif NNGRRN (R=A or G) (SEQ ID NO: 8) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from that sequence. In certain embodiments, a Cas9 molecule of S. aureus recognizes the sequence motif NNGRRT (R=A or G) (SEQ ID NO: 9) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from that sequence. In certain embodiments, a Cas9 molecule of S. aureus recognizes the sequence motif NNGRRV (R=A or G; V=A or C or G) (SEQ ID NO: 10) and directs cleavage of a target nucleic acid sequence 1 to 10, for example, 3 to 5, bp upstream from that sequence. A Cas9 molecule derived from Neisseria meningitidis (NmCas9) normally has a native PAM of NNNNGATT (SEQ ID NO: 11), but may have activity across a variety of PAMs, including a highly degenerate NNNNGNNN PAM (SEQ ID NO: 12) (Esvelt et al. Nature Methods 2013 doi:10.1038/nmeth.2681). In the aforementioned embodiments, N can be any nucleotide residue, for example, any of A, G, C, or T. Cas9 molecules can be engineered to alter the PAM specificity of the Cas9 molecule.

In some embodiments, the Cas9 protein recognizes a PAM sequence of or comprising NGG (SEQ ID NO: 2) or NGA (SEQ ID NO: 13) or NNNRRT (R=A or G) (SEQ ID NO: 14) or ATTCCT (SEQ ID NO: 15) or NGAN (SEQ ID NO: 16) or NGNG (SEQ ID NO: 17). In some embodiments, the Cas9 protein is a Cas9 protein of S. aureus and recognizes the sequence motif NNGRR (R=A or G) (SEQ ID NO: 7), NNGRRN (R=A or G) (SEQ ID NO: 8), NNGRRT (R=A or G) (SEQ ID NO: 9), or NNGRRV (R=A or G) (V=A or G or C) (SEQ ID NO: 10). In the aforementioned embodiments, N can be any nucleotide residue, for example, any of A, G, C, or T. In some embodiments, the PAM sequence comprises ATTCCT (SEQ ID NO: 15).

Additionally or alternatively, a nucleic acid encoding a Cas9 molecule or Cas9 polypeptide may comprise a nuclear localization sequence (NLS). Nuclear localization sequences are known in the art, for example, SV40 NLS (Pro-Lys-Lys-Lys-Arg-Lys-Val; SEQ ID NO: 61.

In some embodiments, the at least one Cas9 molecule is a mutant Cas9 molecule. The Cas9 protein can be mutated so that the nuclease activity is inactivated. An inactivated Cas9 protein (“iCas9”, also referred to as “dCas9”) with no endonuclease activity has been targeted to genes in bacteria, yeast, and human cells by gRNAs to silence gene expression through steric hindrance. Exemplary mutations with reference to the S. pyogenes Cas9 sequence to inactivate the nuclease activity include: D10A, E762A, H840A, N854A, N863A and/or D986A. A S. pyogenes Cas9 protein with the D10A mutation may comprise an amino acid sequence of SEQ ID NO: 131. A S. pyogenes Cas9 protein with D10A and H849A mutations may comprise an amino acid sequence of SEQ ID NO: 132. Exemplary mutations with reference to the S. aureus Cas9 sequence to inactivate the nuclease activity include D10A and N580A. In certain embodiments, the mutant S. aureus Cas9 molecule comprises a D10A mutation. The nucleotide sequence encoding this mutant S. aureus Cas9 is set forth in SEQ ID NO: 133. In certain embodiments, the mutant S. aureus Cas9 molecule comprises a N580A mutation. The nucleotide sequence encoding this mutant S. aureus Cas9 molecule is set forth in SEQ ID NO: 134.

In some embodiments, the Cas9 protein is a VQR variant. The VQR variant of Cas9 is a mutant with a different PAM recognition, as detailed in Kleinstiver, et al. (Nature 2015, 523, 481-485, incorporated herein by reference).

A polynucleotide encoding a Cas9 molecule can be a synthetic polynucleotide. For example, the synthetic polynucleotide can be chemically modified. The synthetic polynucleotide can be codon optimized, for example, at least one non-common codon or less-common codon has been replaced by a common codon. For example, the synthetic polynucleotide can direct the synthesis of an optimized messenger mRNA, for example, optimized for expression in a mammalian expression system, as described herein. An exemplary codon optimized nucleic acid sequence encoding a Cas9 molecule of S. pyogenes is set forth in SEQ ID NO: 20. Exemplary codon optimized nucleic acid sequences encoding a Cas9 molecule of S. aureus, and optionally containing nuclear localization sequences (NLSs), are set forth in SEQ ID NOs: 21-27. Another exemplary codon optimized nucleic acid sequence encoding a Cas9 molecule of S. aureus comprises the nucleotides 1293-4451 of SEQ ID NO: 28.

b. Cas Fusion Protein

Alternatively or additionally, the CRISPR/Cas9-based gene editing system can include a fusion protein. The fusion protein can comprise two heterologous polypeptide domains. The first polypeptide domain comprises a Cas9 protein or a mutant Cas9 protein. The first polypeptide domain is fused to at least one second polypeptide domain. The second polypeptide domain has a different activity that what is endogenous to Cas9 protein. For example, the second polypeptide domain may have an activity such as transcription activation activity, transcription repression activity, transcription release factor activity, histone modification activity, nuclease activity, nucleic acid association activity, methylase activity, demethylase activity, acetylation activity, and/or deacetylation activity. The activity of the second polypeptide domain may be direct or indirect. The second polypeptide domain may have this activity itself (direct), or it may recruit and/or interact with a polypeptide domain that has this activity (indirect). The second polypeptide domain may be at the C-terminal end of the first polypeptide domain, or at the N-terminal end of the first polypeptide domain, or a combination thereof. The fusion protein may include one second polypeptide domain. The fusion protein may include two of the second polypeptide domains. For example, the fusion protein may include a second polypeptide domain at the N-terminal end of the first polypeptide domain as well as a second polypeptide domain at the C-terminal end of the first polypeptide domain. In other embodiments, the fusion protein may include a single first polypeptide domain and more than one (for example, two or three) second polypeptide domains in tandem.

The linkage from the first polypeptide domain to the second polypeptide domain can be through reversible or irreversible covalent linkage or through a non-covalent linkage, as long as the linker does not interfere with the function of the second polypeptide domain. For example, a Cas polypeptide can be linked to a second polypeptide domain as part of a fusion protein. As another example, they can be linked through reversible non-covalent interactions such as avidin (or streptavidin)-biotin interaction, histidine-divalent metal ion interaction (such as, Ni, Co, Cu, Fe), interactions between multimerization (such as, dimerization) domains, or glutathione S-transferase (GST)-glutathione interaction. As yet another example, they can be linked covalently but reversibly with linkers such as dibromomaleimide (DBM) or amino-thiol conjugation.

In some embodiments, the fusion protein includes at least one linker. A linker may be included anywhere in the polypeptide sequence of the fusion protein, for example, between the first and second polypeptide domains. A linker may be of any length and design to promote or restrict the mobility of components in the fusion protein. A linker may comprise any amino acid sequence of about 2 to about 100, about 5 to about 80, about 10 to about 60, or about 20 to about 50 amino acids. A linker may comprise an amino acid sequence of at least about 2, 3, 4, 5, 10, 15, 20, 25, or 30 amino acids. A linker may comprise an amino acid sequence of less than about 100, 90, 80, 70, 60, 50, or 40 amino acids. A linker may include sequential or tandem repeats of an amino acid sequence that is 2 to 20 amino acids in length. Linkers may include, for example, a GS linker (Gly-Gly-Gly-Gly-Ser)n, wherein n is an integer between 0 and 10 (SEQ ID NO: 135). In a GS linker, n can be adjusted to optimize the linker length and achieve appropriate separation of the functional domains. Other examples of linkers may include, for example, Gly-Gly-Gly-Gly-Gly (SEQ ID NO: 136), Gly-Gly-Ala-Gly-Gly (SEQ ID NO: 137), Gly/Ser rich linkers such as Gly-Gly-Gly-Gly-Ser-Ser-Ser (SEQ ID NO: 138), or Gly/Ala rich linkers such as Gly-Gly-Gly-Gly-Ala-Ala-Ala (SEQ ID NO: 139).

In some embodiments, the second polypeptide domain has nuclease activity. A second polypeptide domain having nuclease activity may comprise, for example, FokI or TevI.

i) Transcription Activation Activity

The second polypeptide domain can have transcription activation activity, for example, a transactivation domain. For example, gene expression of endogenous mammalian genes, such as human genes, can be achieved by targeting a fusion protein of a first polypeptide domain, such as dCas9, and a transactivation domain to mammalian promoters via combinations of gRNAs. The transactivation domain can include a VP16 protein, multiple VP16 proteins, such as a VP48 domain or VP64 domain, p65 domain of NF kappa B transcription activator activity, TET1, VPR, VPH, Rta, and/or p300. For example, the fusion protein may comprise dCas9-p300. In some embodiments, p300 comprises a polypeptide having the amino acid sequence of SEQ ID NO: 140 or SEQ ID NO: 141. In other embodiments, the fusion protein comprises dCas9-VP64. In other embodiments, the fusion protein comprises VP64-dCas9-VP64. VP64-dCas9-VP64 may comprise a polypeptide having the amino acid sequence of SEQ ID NO: 142, encoded by the polynucleotide of SEQ ID NO: 143. VPH may comprise a polypeptide having the amino acid sequence of SEQ ID NO: 144, encoded by the polynucleotide of SEQ ID NO: 145. VPR may comprise a polypeptide having the amino acid sequence of SEQ ID NO: 146, encoded by the polynucleotide of SEQ ID NO: 147.

ii) Transcription Repression Activity

The second polypeptide domain can have transcription repression activity. Non-limiting examples of repressors include Kruppel associated box activity such as a KRAB domain or KRAB, MECP2, EED, ERF repressor domain (ERD), Mad mSIN3 interaction domain (SID) or Mad-SID repressor domain, SID4× repressor domain, MxiI repressor domain, SUV39H1, SUV39H2, G9A, ESET/SETBD1, Cir4, Su(var)3-9, Pr-SET7/8, SUV4-20H1, PR-set7, Suv4-20, Set9, EZH2, RIZ1, JMJD2A/JHDM3A, JMJD2B, JMJ2D2C/GASC1, JMJD2D, Rph1, JARID1A/RBP2, JARID1B/PLU-1, JARID1C/SMCX, JARID1D/SMCY, Lid, Jhn2, Jmj2, HDAC1, HDAC2, HDAC3, HDAC8, Rpd3, Hos1, Cir6, HDAC4, HDAC5, HDAC7, HDAC9, Hda1, Cir3, SIRT1, SIRT2, Sir2, Hst1, Hst2, Hst3, Hst4, HDAC11, DNMT1, DNMT3a/3b, DNMT3A-3L, MET1, DRM3, ZMET2, CMT1, CMT2, Laminin A, Laminin B, CTCF, and/or a domain having TATA box binding protein activity, or a combination thereof. In some embodiments, the second polypeptide domain has a KRAB domain activity, ERF repressor domain activity, MxiI repressor domain activity, SID4× repressor domain activity, Mad-SID repressor domain activity, DNMT3A or DNMT3L or fusion thereof activity, LSD1 histone demethylase activity, or TATA box binding protein activity. In some embodiments, the polypeptide domain comprises KRAB. For example, the fusion protein may be S. pyogenes dCas9-KRAB (polynucleotide sequence SEQ ID NO: 148; protein sequence SEQ ID NO: 149). The fusion protein may be S. aureus dCas9-KRAB (polynucleotide sequence SEQ ID NO: 150; protein sequence SEQ ID NO: 151).

iii) Transcription Release Factor Activity

The second polypeptide domain can have transcription release factor activity. The second polypeptide domain can have eukaryotic release factor 1 (ERF1) activity or eukaryotic release factor 3 (ERF3) activity.

iv) Histone Modification Activity

The second polypeptide domain can have histone modification activity. The second polypeptide domain can have histone deacetylase, histone acetyltransferase, histone demethylase, or histone methyltransferase activity. The histone acetyltransferase may be p300 or CREB-binding protein (CBP) protein, or fragments thereof. For example, the fusion protein may be dCas9-p300. In some embodiments, p300 comprises a polypeptide of SEQ ID NO: 140 or SEQ ID NO: 141.

v) Nuclease Activity

The second polypeptide domain can have nuclease activity that is different from the nuclease activity of the Cas9 protein. A nuclease, or a protein having nuclease activity, is an enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids. Nucleases are usually further divided into endonucleases and exonucleases, although some of the enzymes may fall in both categories. Well known nucleases include deoxyribonuclease and ribonuclease. A second polypeptide domain having nuclease activity may comprise, for example, FokI and/or TevI.

vi) Nucleic Acid Association Activity

The second polypeptide domain can have nucleic acid association activity or nucleic acid binding protein-DNA-binding domain (DBD). A DBD is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a general affinity to DNA. A nucleic acid association region may be selected from helix-turn-helix region, leucine zipper region, winged helix region, winged helix-turn-helix region, helix-loop-helix region, immunoglobulin fold, B3 domain, Zinc finger, HMG-box, Wor3 domain, and TAL effector DNA-binding domain.

vii) Methylase Activity

The second polypeptide domain can have methylase activity, which involves transferring a methyl group to DNA, RNA, protein, small molecule, cytosine, or adenine. In some embodiments, the second polypeptide domain includes a DNA methyltransferase.

viii) Demethylase Activity

The second polypeptide domain can have demethylase activity. The second polypeptide domain can include an enzyme that removes methyl (CH3-) groups from nucleic acids, proteins (in particular histones), and other molecules. Alternatively, the second polypeptide can convert the methyl group to hydroxymethylcytosine in a mechanism for demethylating DNA. The second polypeptide can catalyze this reaction. For example, the second polypeptide that catalyzes this reaction can be Tet1, also known as Tet1CD (Ten-eleven translocation methylcytosine dioxygenase 1; polynucleotide sequence SEQ ID NO: 152; amino acid sequence SEQ ID NO: 153). In some embodiments, the second polypeptide domain has histone demethylase activity. In some embodiments, the second polypeptide domain has DNA demethylase activity.

c. Guide RNA (gRNA)

The CRISPR/Cas-based gene editing system includes at least one gRNA molecule. For example, the CRISPR/Cas-based gene editing system may include two gRNA molecules. The at least one gRNA molecule can bind and recognize a target region. The gRNA provides the targeting of a CRISPR/Cas9-based gene editing system. The gRNA is a fusion of two noncoding RNAs: a crRNA and a tracrRNA. gRNA mimics the naturally occurring crRNA:tracrRNA duplex involved in the Type II Effector system. This duplex, which may include, for example, a 42-nucleotide crRNA and a 75-nucleotide tracrRNA, acts as a guide for the Cas9 to bind, and in some cases, cleave the target nucleic acid. The gRNA may target any desired DNA sequence by exchanging the sequence encoding a protospacer which confers targeting specificity through complementary base pairing with the desired DNA target. The CRISPR/Cas9-based gene editing system may include at least one gRNA, wherein the gRNAs target different DNA sequences. The target DNA sequences may be overlapping. The “target region” or “target sequence” or “protospacer” refers to the region of the target gene to which the CRISPR/Cas9-based gene editing system targets and binds or hybridizes to. The portion of the gRNA that targets the target sequence in the genome may be referred to as the “targeting sequence” or “targeting portion” or “targeting domain.” The CRISPR/Cas9-based gene editing system may include at least one gRNA, wherein the gRNAs target or hybridize to different DNA sequences. The target DNA sequences may be overlapping. The gRNA may comprise at its 5′ end the targeting domain that is sufficiently complementary to the target region to be able to hybridize to, for example, about 10 to about 20 nucleotides of the target region of the target gene, when it is followed by an appropriate Protospacer Adjacent Motif (PAM). The target sequence or protospacer is followed by a PAM sequence at the 3′ end of the target sequence or protospacer in the genome. Different Type II systems have differing PAM requirements, as detailed above.

“Protospacer” or “gRNA spacer” may refer to the region of the target sequence to which the CRISPR/Cas9-based gene editing system targets and binds or hybridizes; “protospacer” or “gRNA spacer” may also refer to the portion of the gRNA that is complementary to the targeted sequence in the genome. The protospacer may be, for example, 18 nucleotides or base pairs, 19 nucleotides or base pairs, 20 nucleotides or base pairs, 21 nucleotides or base pairs, 22 nucleotides or base pairs, 23 nucleotides or base pairs, 24 nucleotides or base pairs, 25 nucleotides or base pairs, 26 nucleotides or base pairs, or 27 nucleotides or base pairs in length.

The gRNA may include a gRNA scaffold. A gRNA scaffold facilitates Cas9 binding to the gRNA and may facilitate endonuclease activity. The gRNA scaffold is a polynucleotide sequence that follows the portion of the gRNA corresponding to sequence that the gRNA targets. Together, the gRNA targeting portion and gRNA scaffold form one polynucleotide. The constant region of the gRNA may include the sequence of SEQ ID NO: 63 (RNA), which is encoded by a sequence comprising SEQ ID NO: 62 (DNA).

The targeting domain of the gRNA does not need to be perfectly complementary to the target region of the target DNA. In some embodiments, the targeting domain of the gRNA is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or at least 99% complementary to (or has 1, 2 or 3 mismatches compared to) the target region over a length of, such as, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides. For example, the DNA-targeting domain of the gRNA may be at least 80% complementary over at least 18 nucleotides of the target region. The target region may be on either strand of the target DNA.

The gRNA may target and bind or hybridize to a region or fragment of the dystrophin gene. The gRNA may target and bind or hybridize to a region or fragment of a mutant dystrophin gene. The gRNA may target and bind or hybridize to a region or fragment of a wild-type dystrophin gene. The gRNA may target an intron. The gRNA may target an intron that is juxtaposed with or adjacent to an exon of the dystrophin gene. The gRNA may target an intron that is juxtaposed with or adjacent to an exon of a mutant dystrophin gene. A fragment may be about 5 to about 200, about 10 to about 200, about 5 to about 300, or about 10 to about 300 nucleotides in length. A fragment may be at least about 5, at least about 10, at least about 15, at least about 20, at least about 30, at least about 40, at least about 50, or at least about 100 nucleotides in length. gRNA may target a fragment or portion of the dystrophin gene that comprises a mutation or deletion, or a sequence proximal or adjacent to or juxtapositioned thereto. In some embodiments, the gRNA targets intron 51. Intron 51 of the human dystrophin gene may comprise a polynucleotide sequence of SEQ ID NO: 128. In some embodiments, the gRNA targets intron 44. Intron 44 of the human dystrophin gene may comprise a polynucleotide sequence of SEQ ID NO: 156.

The gRNA may target and/or bind to and/or hybridize to a polynucleotide sequence comprising at least one of SEQ ID NOs: 29-51 and 87, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA may be encoded by a polynucleotide sequence comprising at least one of SEQ ID NOs: 29-51 and 87, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA may comprise a polynucleotide sequence comprising at least one of SEQ ID NOs: 29-51 and 87, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA may comprise a polynucleotide sequence comprising at least one of SEQ ID NOs: 64-86, 88, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA spacer may comprise a polynucleotide sequence comprising at least one of SEQ ID NOs: 29-51, 87, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA spacer may be encoded by a polynucleotide sequence comprising at least one of SEQ ID NOs: 29-51, 87, or a complement thereof, or a variant thereof, or a truncation thereof. A truncation may be 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides shorter than the reference sequence. In some embodiments, the gRNA scaffold is encoded by the polynucleotide sequence of SEQ ID NO: 52, or a complement thereof.

The gRNA may target and/or bind to and/or hybridize to a polynucleotide sequence comprising at least one of SEQ ID NOs: 157-170, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA may be encoded by a polynucleotide sequence comprising at least one of SEQ ID NOs: 157-170, or a complement thereof, or a variant thereof, or a truncation thereof. The gRNA may comprise a polynucleotide sequence comprising at least one of SEQ ID NOs: 171-184, or a complement thereof, or a variant thereof, or a truncation thereof. A truncation may be 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides shorter than the reference sequence.

As described above, the gRNA molecule comprises a targeting domain (also referred to as targeting sequence), which is a polynucleotide sequence complementary to the target DNA sequence. The gRNA may comprise a “G” at the 5′ end of the targeting domain or complementary polynucleotide sequence. The CRISPR/Cas9-based gene editing system may use gRNAs of varying sequences and lengths. The targeting domain of a gRNA molecule may comprise at least a 10 base pair, at least a 11 base pair, at least a 12 base pair, at least a 13 base pair, at least a 14 base pair, at least a 15 base pair, at least a 16 base pair, at least a 17 base pair, at least a 18 base pair, at least a 19 base pair, at least a 20 base pair, at least a 21 base pair, at least a 22 base pair, at least a 23 base pair, at least a 24 base pair, at least a 25 base pair, at least a 30 base pair, or at least a 35 base pair complementary polynucleotide sequence of the target DNA sequence followed by a PAM sequence. In certain embodiments, the targeting domain of a gRNA molecule has 19-25 nucleotides in length. In certain embodiments, the targeting domain of a gRNA molecule is 20 nucleotides in length. In certain embodiments, the targeting domain of a gRNA molecule is 21 nucleotides in length. In certain embodiments, the targeting domain of a gRNA molecule is 22 nucleotides in length. In certain embodiments, the targeting domain of a gRNA molecule is 23 nucleotides in length.

The number of gRNA molecules that may be included in the CRISPR/Cas9-based gene editing system can be at least 1 gRNA, at least 2 different gRNAs, at least 3 different gRNAs, at least 4 different gRNAs, at least 5 different gRNAs, at least 6 different gRNAs, at least 7 different gRNAs, at least 8 different gRNAs, at least 9 different gRNAs, at least 10 different gRNAs, at least 11 different gRNAs, at least 12 different gRNAs, at least 13 different gRNAs, at least 14 different gRNAs, at least 15 different gRNAs, at least 16 different gRNAs, at least 17 different gRNAs, at least 18 different gRNAs, at least 18 different gRNAs, at least 20 different gRNAs, at least 25 different gRNAs, at least 30 different gRNAs, at least 35 different gRNAs, at least 40 different gRNAs, at least 45 different gRNAs, or at least 50 different gRNAs. The number of gRNA molecules that may be included in the CRISPR/Cas9-based gene editing system can be less than 50 different gRNAs, less than 45 different gRNAs, less than 40 different gRNAs, less than 35 different gRNAs, less than 30 different gRNAs, less than 25 different gRNAs, less than 20 different gRNAs, less than 19 different gRNAs, less than 18 different gRNAs, less than 17 different gRNAs, less than 16 different gRNAs, less than 15 different gRNAs, less than 14 different gRNAs, less than 13 different gRNAs, less than 12 different gRNAs, less than 11 different gRNAs, less than 10 different gRNAs, less than 9 different gRNAs, less than 8 different gRNAs, less than 7 different gRNAs, less than 6 different gRNAs, less than 5 different gRNAs, less than 4 different gRNAs, less than 3 different gRNAs, or less than 2 different gRNAs. The number of gRNAs that may be included in the CRISPR/Cas9-based gene editing system can be between at least 1 gRNA to at least 50 different gRNAs, at least 1 gRNA to at least 45 different gRNAs, at least 1 gRNA to at least 40 different gRNAs, at least 1 gRNA to at least 35 different gRNAs, at least 1 gRNA to at least 30 different gRNAs, at least 1 gRNA to at least 25 different gRNAs, at least 1 gRNA to at least 20 different gRNAs, at least 1 gRNA to at least 16 different gRNAs, at least 1 gRNA to at least 12 different gRNAs, at least 1 gRNA to at least 8 different gRNAs, at least 1 gRNA to at least 4 different gRNAs, at least 4 gRNAs to at least 50 different gRNAs, at least 4 different gRNAs to at least 45 different gRNAs, at least 4 different gRNAs to at least 40 different gRNAs, at least 4 different gRNAs to at least 35 different gRNAs, at least 4 different gRNAs to at least 30 different gRNAs, at least 4 different gRNAs to at least 25 different gRNAs, at least 4 different gRNAs to at least 20 different gRNAs, at least 4 different gRNAs to at least 16 different gRNAs, at least 4 different gRNAs to at least 12 different gRNAs, at least 4 different gRNAs to at least 8 different gRNAs, at least 8 different gRNAs to at least 50 different gRNAs, at least 8 different gRNAs to at least 45 different gRNAs, at least 8 different gRNAs to at least 40 different gRNAs, at least 8 different gRNAs to at least 35 different gRNAs, 8 different gRNAs to at least 30 different gRNAs, at least 8 different gRNAs to at least 25 different gRNAs, 8 different gRNAs to at least 20 different gRNAs, at least 8 different gRNAs to at least 16 different gRNAs, or 8 different gRNAs to at least 12 different gRNAs.

d. Donor Sequence

The CRISPR/Cas9-based gene editing system may include at least one donor sequence. A donor sequence may comprise a fragment of a dystrophin gene. A donor sequence may comprise a fragment of a wild-type dystrophin gene. For example, a donor sequence may comprise a nucleic acid sequence encoding an exon or any combination of exons of the dystrophin gene. The donor sequence may comprise an exon of the wild-type dystrophin gene or a functional equivalent thereof. The donor sequence may comprise one or more exons of the wild-type dystrophin gene or a functional equivalent thereof. The donor sequence may comprise one or more exons and/or introns of the wild-type dystrophin gene or a functional equivalent thereof. The donor sequence may comprise one or more exons of the wild-type dystrophin gene selected from exon 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, and 79, or a combination thereof, or a functional equivalent thereof. In some embodiments, the donor sequence comprises exon 52. In some embodiments, the donor sequence includes exons 52-79. In some embodiments, the donor sequence includes exons 45-79. In some embodiments, exons 52-79 is referred to as a super exon. In some embodiments, exons 45-79 is referred to as a super exon. The donor sequence may further include at least one additional polynucleotide corresponding to intron sequences surrounding or near the exon(s) to be inserted. The donor sequence may further include at least one additional polynucleotide corresponding to intron sequences surrounding or near exon 52. The donor sequence may comprise a polynucleotide sequence selected from SEQ ID NOs: 53-56 and 154-155. In some embodiments, the donor sequence includes exons 52-79 and the donor sequence comprises a polynucleotide sequence selected from SEQ ID NOs: 53-56. In some embodiments, the donor sequence includes exons 45-79 and the donor sequence comprises a polynucleotide sequence selected from SEQ ID NOs: 154-155.

The donor sequence may be flanked on both sides by a gRNA spacer and/or a PAM sequence. The donor sequence may be flanked on the 5′-end and the 3′-end by a gRNA spacer and/or a PAM sequence. The gRNA spacer and/or a PAM sequence that flank the donor sequence directs the Cas9 protein to cut or excise the donor fragment from the CRISPR/Cas9-based gene editing system. This may thereby liberate the donor sequence for insertion into the genome. In some embodiments, the targeting region of the gRNA is complementary to the gRNA spacer that flanks the donor sequence. The gRNA spacer may comprise or be encoded by a polynucleotide selected from SEQ ID NO: 29-51 and 87 and 157-170.

The gRNA and donor sequence may be present in a variety of molar ratios. The molar ratio between the gRNA and donor sequence may be 1:1, or 1:5, or from 5:1 to 1:10, or from 1:1 to 1:5. The molar ratio between the gRNA and donor sequence may be at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, or at least 1:20. The molar ratio between the gRNA and donor sequence may be less than 20:1, less than 15:1, less than 10:1, less than 9:1, less than 8:1, less than 7:1, less than 6:1, less than 5:1, less than 4:1, less than 3:1, less than 2:1, or less than 1:1.

e. Repair Pathways

The CRISPR/Cas9-based gene editing system may be used to introduce site-specific double strand breaks at targeted genomic loci, such as an intron or exon of a dystrophin gene. Site-specific double-strand breaks are created when the CRISPR/Cas9-based gene editing system binds to a target DNA sequences, thereby permitting cleavage of the target DNA. This DNA cleavage may stimulate the natural DNA-repair machinery, leading to one of two possible repair pathways: homology-directed repair (HDR) or the non-homologous end joining (NHEJ) pathway.

i) Homology-Directed Repair (HDR)

Restoration of protein expression from a gene may involve homology-directed repair (HDR). A donor template may be administered to a cell. The donor template may include a nucleotide sequence encoding a full-functional protein or a partially functional protein. In such embodiments, the donor template may include fully functional gene construct for restoring a mutant gene, or a fragment of the gene that after homology-directed repair, leads to restoration of the mutant gene. In other embodiments, the donor template may include a nucleotide sequence encoding a mutated version of an inhibitory regulatory element of a gene. Mutations may include, for example, nucleotide substitutions, insertions, deletions, or a combination thereof. In such embodiments, introduced mutation(s) into the inhibitory regulatory element of the gene may reduce the transcription of or binding to the inhibitory regulatory element.

ii) NHEJ

Restoration of protein expression from gene may be through template-free NHEJ-mediated DNA repair. In certain embodiments, NHEJ is a nuclease mediated NHEJ, which in certain embodiments, refers to NHEJ that is initiated a Cas9 molecule that cuts double stranded DNA. The method comprises administering a presently disclosed CRISPR/Cas9-based gene editing system or a composition comprising thereof to a subject for gene editing.

Nuclease mediated NHEJ may correct a mutated target gene and offer several potential advantages over the HDR pathway. For example, NHEJ does not require a donor template, which may cause nonspecific insertional mutagenesis. In contrast to HDR, NHEJ operates efficiently in all stages of the cell cycle and therefore may be effectively exploited in both cycling and post-mitotic cells, such as muscle fibers. This provides a robust, permanent gene restoration alternative to oligonucleotide-based exon skipping or pharmacologic forced read-through of stop codons and could theoretically require as few as one drug treatment.

4. GENETIC CONSTRUCTS

The CRISPR/Cas9-based gene editing system may be encoded by or comprised within one or more genetic constructs. The CRISPR/Cas9-based gene editing system may comprise one or more genetic constructs. The genetic construct, such as a plasmid or expression vector, may comprise a nucleic acid that encodes the CRISPR/Cas9-based gene editing system and/or at least one of the gRNAs and/or a donor sequence. In certain embodiments, a genetic construct encodes one gRNA molecule, i.e., a first gRNA molecule, and optionally a Cas9 molecule or fusion protein. In some embodiments, a genetic construct encodes two gRNA molecules, i.e., a first gRNA molecule and a second gRNA molecule, and optionally a Cas9 molecule or fusion protein. In some embodiments, a first genetic construct encodes one gRNA molecule, i.e., a first gRNA molecule, and optionally a Cas9 molecule or fusion protein, and a second genetic construct encodes one gRNA molecule, i.e., a second gRNA molecule, and optionally a Cas9 molecule or fusion protein. In some embodiments, a first genetic construct encodes one gRNA molecule and one donor sequence, and a second genetic construct encodes a Cas9 molecule or fusion protein. In some embodiments, a first genetic construct encodes one gRNA molecule and a Cas9 molecule or fusion protein, and a second genetic construct encodes one donor sequence.

Genetic constructs may include polynucleotides such as vectors and plasmids. The genetic construct may be a linear minichromosome including centromere, telomeres, or plasmids or cosmids. The vector may be an expression vectors or system to produce protein by routine techniques and readily available starting materials including Sambrook et al., Molecular Cloning and Laboratory Manual, Second Ed., Cold Spring Harbor (1989), which is incorporated fully by reference. The construct may be recombinant. The genetic construct may be part of a genome of a recombinant viral vector, including recombinant lentivirus, recombinant adenovirus, and recombinant adenovirus associated virus. The genetic construct may comprise regulatory elements for gene expression of the coding sequences of the nucleic acid. The regulatory elements may be a promoter, an enhancer, an initiation codon, a stop codon, or a polyadenylation signal.

The genetic construct may comprise heterologous nucleic acid encoding the CRISPR/Cas-based gene editing system and may further comprise an initiation codon, which may be upstream of the CRISPR/Cas-based gene editing system coding sequence, and a stop codon, which may be downstream of the CRISPR/Cas-based gene editing system coding sequence. The genetic construct may include more than one stop codon, which may be downstream of the CRISPR/Cas-based gene editing system coding sequence. In some embodiments, the genetic construct includes 1, 2, 3, 4, or 5 stop codons. In some embodiments, the genetic construct includes 1, 2, 3, 4, or 5 stop codons downstream of the sequence encoding the donor sequence. A stop codon may be in-frame with a coding sequence in the CRISPR/Cas-based gene editing system. For example, one or more stop codons may be in-frame with the donor sequence. The genetic construct may include one or more stop codons that are out of frame of a coding sequence in the CRISPR/Cas-based gene editing system. For example, one stop codon may be in-frame with the donor sequence, and two other stop codons may be included that are in the other two possible reading frames. A genetic construct may include a stop codon for all three potential reading frames. The initiation and termination codon may be in frame with the CRISPR/Cas-based gene editing system coding sequence.

The vector may also comprise a promoter that is operably linked to the CRISPR/Cas-based gene editing system coding sequence. The promoter may be a constitutive promoter, an inducible promoter, a repressible promoter, or a regulatable promoter. The promoter may be a ubiquitous promoter. The promoter may be a tissue-specific promoter. The tissue specific promoter may be a muscle specific promoter. The tissue specific promoter may be a skin specific promoter. The CRISPR/Cas-based gene editing system may be under the light-inducible or chemically inducible control to enable the dynamic control of gene/genome editing in space and time. The promoter operably linked to the CRISPR/Cas-based gene editing system coding sequence may be a promoter from simian virus 40 (SV40), a mouse mammary tumor virus (MMTV) promoter, a human immunodeficiency virus (HIV) promoter such as the bovine immunodeficiency virus (BIV) long terminal repeat (LTR) promoter, a Moloney virus promoter, an avian leukosis virus (ALV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter, Epstein Barr virus (EBV) promoter, or a Rous sarcoma virus (RSV) promoter. The promoter may also be a promoter from a human gene such as human ubiquitin C (hUbC), human actin, human myosin, human hemoglobin, human muscle creatine, or human metalothionein. Examples of a tissue specific promoter, such as a muscle or skin specific promoter, natural or synthetic, are described in U.S. Patent Application Publication No. US20040175727, the contents of which are incorporated herein in its entirety. The promoter may be a CK8 promoter, a Spc512 promoter, a MHCK7 promoter, for example.

The genetic construct may also comprise a polyadenylation signal, which may be downstream of the CRISPR/Cas-based gene editing system. The polyadenylation signal may be a SV40 polyadenylation signal, LTR polyadenylation signal, bovine growth hormone (bGH) polyadenylation signal, human growth hormone (hGH) polyadenylation signal, or human β-globin polyadenylation signal. The SV40 polyadenylation signal may be a polyadenylation signal from a pCEP4 vector (Invitrogen, San Diego, Calif.).

Coding sequences in the genetic construct may be optimized for stability and high levels of expression. In some instances, codons are selected to reduce secondary structure formation of the RNA such as that formed due to intramolecular bonding.

The genetic construct may also comprise an enhancer upstream of the CRISPR/Cas-based gene editing system or gRNAs. The enhancer may be necessary for DNA expression. The enhancer may be human actin, human myosin, human hemoglobin, human muscle creatine or a viral enhancer such as one from CMV, HA, RSV, or EBV. Polynucleotide function enhancers are described in U.S. Pat. Nos. 5,593,972, 5,962,428, and WO94/016737, the contents of each are fully incorporated by reference. The genetic construct may also comprise a mammalian origin of replication in order to maintain the vector extrachromosomally and produce multiple copies of the vector in a cell. The genetic construct may also comprise a regulatory sequence, which may be well suited for gene expression in a mammalian or human cell into which the vector is administered. The genetic construct may also comprise a reporter gene, such as green fluorescent protein (“GFP”) and/or a selectable marker, such as hygromycin (“Hygro”).

The genetic construct may be useful for transfecting cells with nucleic acid encoding the CRISPR/Cas-based gene editing system, which the transformed host cell is cultured and maintained under conditions wherein expression of the CRISPR/Cas-based gene editing system takes place. The genetic construct may be transformed or transduced into a cell. The genetic construct may be formulated into any suitable type of delivery vehicle including, for example, a viral vector, lentiviral expression, mRNA electroporation, and lipid-mediated transfection for delivery into a cell. The genetic construct may be part of the genetic material in attenuated live microorganisms or recombinant microbial vectors which live in cells. The genetic construct may be present in the cell as a functioning extrachromosomal molecule.

Further provided herein is a cell transformed or transduced with a system or component thereof as detailed herein. Suitable cell types are detailed herein. In some embodiments, the cell is a stem cell. The stem cell may be a human stem cell. In some embodiments, the cell is an embryonic stem cell. The stem cell may be a human pluripotent stem cell (iPSCs). Further provided are stem cell-derived neurons, such as neurons derived from iPSCs transformed or transduced with a DNA targeting system or component thereof as detailed herein.

a. Viral Vectors

A genetic construct may be a viral vector. Further provided herein is a viral delivery system. Viral delivery systems may include, for example, lentivirus, retrovirus, adenovirus, mRNA electroporation, or nanoparticles. In some embodiments, the vector is a modified lentiviral vector. In some embodiments, the viral vector is an adeno-associated virus (AAV) vector. The AAV vector is a small virus belonging to the genus Dependovirus of the Parvoviridae family that infects humans and some other primate species.

AAV vectors may be used to deliver CRISPR/Cas9-based gene editing systems using various construct configurations. For example, AAV vectors may deliver Cas9 or fusion protein and gRNA expression cassettes on separate vectors or on the same vector. Alternatively, if the small Cas9 proteins or fusion proteins, derived from species such as Staphylococcus aureus or Neisseria meningitidis, are used then both the Cas9 and up to two gRNA expression cassettes may be combined in a single AAV vector. In some embodiments, the AAV vector has a 4.7 kb packaging limit.

In some embodiments, the AAV vector is a modified AAV vector. The modified AAV vector may have enhanced cardiac and/or skeletal muscle tissue tropism. The modified AAV vector may be capable of delivering and expressing the CRISPR/Cas9-based gene editing system in the cell of a mammal. For example, the modified AAV vector may be an AAV-SASTG vector (Piacentino et al. Human Gene Therapy 2012, 23, 635-646). The modified AAV vector may be based on one or more of several capsid types, including AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. The modified AAV vector may be based on AAV2 pseudotype with alternative muscle-tropic AAV capsids, such as AAV2/1, AAV2/6, AAV2/7, AAV2/8, AAV2/9, AAV2.5, and AAV/SASTG vectors that efficiently transduce skeletal muscle or cardiac muscle by systemic and local delivery (Seto et al. Current Gene Therapy 2012, 12, 139-151). The modified AAV vector may be AAV2i8G9 (Shen et al. J. Biol. Chem. 2013, 288, 28814-28823).

The genetic construct may comprise a polynucleotide sequence selected from SEQ ID NOs: 57-60. The genetic construct may comprise a polynucleotide sequence selected from SEQ ID NOs: 29-51, 53-56, 87, 154-155, 157-169, and 170, or a complement thereof, or a fragment thereof.

5. PHARMACEUTICAL COMPOSITIONS

Further provided herein are pharmaceutical compositions comprising the above-described genetic constructs or gene editing systems. In some embodiments, the pharmaceutical composition may comprise about 1 ng to about 10 mg of DNA encoding the CRISPR/Cas-based gene editing system. The systems or genetic constructs as detailed herein, or at least one component thereof, may be formulated into pharmaceutical compositions in accordance with standard techniques well known to those skilled in the pharmaceutical art. The pharmaceutical compositions can be formulated according to the mode of administration to be used. In cases where pharmaceutical compositions are injectable pharmaceutical compositions, they are sterile, pyrogen free, and particulate free. An isotonic formulation is preferably used. Generally, additives for isotonicity may include sodium chloride, dextrose, mannitol, sorbitol and lactose. In some cases, isotonic solutions such as phosphate buffered saline are preferred. Stabilizers include gelatin and albumin. In some embodiments, a vasoconstriction agent is added to the formulation.

The composition may further comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be functional molecules as vehicles, adjuvants, carriers, or diluents. The term “pharmaceutically acceptable carrier,” may be a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Pharmaceutically acceptable carriers include, for example, diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, emollients, propellants, humectants, powders, pH adjusting agents, and combinations thereof. The pharmaceutically acceptable excipient may be a transfection facilitating agent, which may include surface active agents, such as immune-stimulating complexes (ISCOMS), Freunds incomplete adjuvant, LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene and squalene, hyaluronic acid, lipids, liposomes, calcium ions, viral proteins, polyanions, polycations, or nanoparticles, or other known transfection facilitating agents. The transfection facilitating agent may be a polyanion, polycation, including poly-L-glutamate (LGS), or lipid. The transfection facilitating agent may be poly-L-glutamate, and more preferably, the poly-L-glutamate may be present in the composition for gene editing in skeletal muscle or cardiac muscle at a concentration less than 6 mg/mL.

6. ADMINISTRATION

The systems or genetic constructs as detailed herein, or at least one component thereof, may be administered or delivered to a cell. Methods of introducing a nucleic acid into a host cell are known in the art, and any known method can be used to introduce a nucleic acid (e.g., an expression construct) into a cell. Suitable methods include, for example, viral or bacteriophage infection, transfection, conjugation, protoplast fusion, polycation or lipid:nucleic acid conjugates, lipofection, electroporation, nucleofection, immunoliposomes, calcium phosphate precipitation, polyethyleneimine (PEI)-mediated transfection, DEAE-dextran mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct micro injection, nanoparticle-mediated nucleic acid delivery, and the like. In some embodiments, the composition may be delivered by mRNA delivery and ribonucleoprotein (RNP) complex delivery. The system, genetic construct, or composition comprising the same, may be electroporated using BioRad Gene Pulser Xcell or Amaxa Nucleofector IIb devices or other electroporation device. Several different buffers may be used, including BioRad electroporation solution, Sigma phosphate-buffered saline product #D8537 (PBS), Invitrogen OptiMEM I (OM), or Amaxa Nucleofector solution V (N.V.). Transfections may include a transfection reagent, such as Lipofectamine 2000.

The systems or genetic constructs as detailed herein, or at least one component thereof, or the pharmaceutical compositions comprising the same, may be administered to a subject. Such compositions can be administered in dosages and by techniques well known to those skilled in the medical arts taking into consideration such factors as the age, sex, weight, and condition of the particular subject, and the route of administration. The presently disclosed systems, or at least one component thereof, genetic constructs, or compositions comprising the same, may be administered to a subject by different routes including orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, intranasal, intravaginal, via inhalation, via buccal administration, intrapleurally, intravenous, intraarterial, intraperitoneal, subcutaneous, intradermally, epidermally, intramuscular, intranasal, intrathecal, intracranial, and intraarticular or combinations thereof. In certain embodiments, the system, genetic construct, or composition comprising the same, is administered to a subject intramuscularly, intravenously, or a combination thereof. The systems, genetic constructs, or compositions comprising the same may be delivered to a subject by several technologies including DNA injection (also referred to as DNA vaccination) with and without in vivo electroporation, liposome mediated, nanoparticle facilitated, recombinant vectors such as recombinant lentivirus, recombinant adenovirus, and recombinant adenovirus associated virus. The composition may be injected into the brain or other component of the central nervous system. The composition may be injected into the skeletal muscle or cardiac muscle. For example, the composition may be injected into the tibialis anterior muscle or tail. For veterinary use, the systems, genetic constructs, or compositions comprising the same may be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian may readily determine the dosing regimen and route of administration that is most appropriate for a particular animal. The systems, genetic constructs, or compositions comprising the same may be administered by traditional syringes, needleless injection devices, “microprojectile bombardment gone guns,” or other physical methods such as electroporation (“EP”), “hydrodynamic method”, or ultrasound. Alternatively, transient in vivo delivery of CRISPR/Cas-based systems by non-viral or non-integrating viral gene transfer, or by direct delivery of purified proteins and gRNAs containing cell-penetrating motifs may enable highly specific correction and/or restoration in situ with minimal or no risk of exogenous DNA integration.

Upon delivery of the presently disclosed systems or genetic constructs as detailed herein, or at least one component thereof, or the pharmaceutical compositions comprising the same, and thereupon the vector into the cells of the subject, the transfected cells may express the gRNA molecule(s) and the Cas9 molecule or fusion protein.

a. Cell Types

Any of the delivery methods and/or routes of administration detailed herein can be utilized with a myriad of cell types. Further provided herein is a cell transformed or transduced with a system or component thereof as detailed herein. For example, provided herein is a cell comprising an isolated polynucleotide encoding a CRISPR/Cas9 system as detailed herein. Suitable cell types are detailed herein, for example, those cell types currently under investigation for cell-based therapies, including, but not limited to, immortalized myoblast cells, such as wild-type and DMD patient derived lines, primal DMD dermal fibroblasts, stem cells such as induced pluripotent stem cells, embryonic stem cell, hematopoietic stem cell, bone marrow-derived progenitors, skeletal muscle progenitors, human skeletal myoblasts from DMD patients, CD 133+ cells, mesoangioblasts, cardiomyocytes, hepatocytes, chondrocytes, mesenchymal progenitor cells, hematopoietic stem cells, smooth muscle cells, and MyoD- or Pax7-transduced cells, or other myogenic progenitor cells. The cell may be a human stem cell. The stem cell may be a human induced pluripotent stem cell (iPSC). The cell may be a muscle cell. Immortalization of human myogenic cells can be used for clonal derivation of genetically corrected myogenic cells. Cells can be modified ex vivo to isolate and expand clonal populations of immortalized DMD myoblasts that include a genetically corrected or restored dystrophin gene and are free of other nuclease-introduced mutations in protein coding regions of the genome.

7. KITS

Provided herein is a kit, which may be used to correct a mutated dystrophin gene and/or restore dystrophin function. The kit comprises genetic constructs or a composition comprising the same, for restoring dystrophin function, as described above, and instructions for using said composition. In some embodiments, the kit comprises at least one gRNA comprising or hybridizing to or targeting or encoded by a polynucleotide sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, a variant thereof, or fragment thereof, and/or at least one gRNA spacer comprising or encoded by a polynucleotide sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, a variant thereof, or fragment thereof, and/or at least one gRNA comprising a polynucleotide sequence selected from SEQ ID NOs: 64-86, 88, 171-184, a complement thereof, a variant thereof, or fragment thereof, and/or a donor sequence comprising a polynucleotide sequence selected from SEQ ID NOs: 53-56, 154, and 155, a complement thereof, a variant thereof, or fragment thereof. The kit may further include instructions for using the CRISPR/Cas-based gene editing system.

Instructions included in kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written on printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internet site that provides the instructions.

The genetic constructs or a composition comprising thereof for restoring dystrophin function may include a modified AAV vector that includes a gRNA molecule(s) and a Cas9 protein or fusion protein, as described above, that specifically binds and cleaves a region of the dystrophin gene. The CRISPR/Cas-based gene editing system, as described above, may be included in the kit to specifically bind and target a particular region, for example, exon 52 or intron 51 or intron 44, in the gene.

8. METHODS

a. Methods for Restoring Dystrophin Function

The CRISPR/Cas9-based gene editing systems provided herein may be used for restoring dystrophin function. The CRISPR/Cas9-based gene editing systems may restore dystrophin function by adding one or more exons to restore the reading frame of dystrophin. Use of the presently disclosed CRISPR/Cas9-based gene editing systems delivered to a target muscle, for example, may restore the expression of a full-functional or partially-functional protein with a repair template or donor DNA, which can replace the entire gene or the region containing the mutation.

Provided herein are methods of restoring dystrophin function. The methods may be used for restoring dystrophin function in a cell or a subject having a mutant dystrophin gene. The methods may include contacting the cell or the subject with a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein. In some embodiments, dystrophin function is restored by insertion of the donor sequence, for example, insertion of exons 52-79 or exons 45-79 of the wild-type dystrophin gene. In some embodiments, the subject is suffering from Duchenne Muscular Dystrophy.

The methods may be used for restoring dystrophin function in a cell or a subject having a disrupted dystrophin gene caused by one or more deleted or mutated exons. The methods may include contacting the cell or the subject with a system as detailed herein, a recombinant polynucleotide as detailed herein, or a vector as detailed herein. In some embodiments, dystrophin function is restored by inserting one or more wild-type exons of dystrophin gene corresponding to the one or more deleted or mutated exons. In some embodiments, dystrophin function is restored by insertion of the donor sequence, for example, insertion of exons 52-79 or exons 45-79 of the wild-type dystrophin gene. In some embodiments, the subject is suffering from Duchenne Muscular Dystrophy.

9. EXAMPLES

The foregoing may be better understood by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention. The present disclosure has multiple aspects and embodiments, illustrated by the appended non-limiting examples.

Example 1 Materials and Methods

Plasmid Design and AAV Production. The ITR-containing Staphylococcus aureus Cas9 (pAAV-SaCas9) expression plasmid was generated by adding a 3×HA epitope to the carboxyl-terminus of SaCas9 using Gibson cloning strategies. The CMV-SaCas9-3×HA-polyA was transferred to a new plasmid (pSaCas9) without ITRs for stability in cell culture experiments. A separate plasmid with a hU6-driven guide RNA cassette (Nelson, C. E., et al. Science 2016, 351, 403-407) (pU6-gRNA) was used with BbsI cloning to screen guides in vitro. For AAV-gRNA-donor plasmids (pAAV-g12-Ex52, pAAV-g7-Ex52, and pAAv-g7-Superexon), gene blocks were synthesized by Integrated DNA technology (IDT) and integrated into ITR-containing plasmids by Gibson cloning strategies. Intact ITRs were verified by SmaI digest before AAV production on all vectors. Multiple batches of AAV2 and AAV9 were produced at Duke University. Titers were measured by qPCR with a plasmid standard curve.

In Vitro gRNA Screening. A panel of gRNAs (TABLE 1) were designed to target intron 51 of the human DMD gene and compared for SaCas9 activity by Surveyor assay in HEK293T cells and DMD patient myoblasts. HEK293T cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen) with 10% Fetal Bovine Serum (FBS, Sigma) and 1% penicillin-streptomycin (P/S, Gibco). Immortalized DMD patient 8036 myoblasts (DM8036 cell line with a deletion of exons 48-50 in the DMD gene)(Mamchaoui, K., et al. Skelet. Muscle 2011, 1, 34) were maintained in skeletal muscle media (PromoCell) with 20% FBS (Sigma), 50 μg/mL fetuin (Sigma), 10 ng/mL human epidermal growth factor (Sigma), 1 ng/mL human basic fibroblast growth factor (bFGF, Sigma), 10 μg/mL human insulin (Sigma), 400 ng/mL dexamethasone (Sigma), 1% GlutaMAX (Invitrogen), and 1% P/S. Cells were incubated at 37° C. with 5% CO₂. HEK293T cells were transfected with 375 ng pSaCas9 and 125 ng pU6-gRNA plasmid using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. DMD myoblasts were electroporated with 10 μg pSaCas9 and 10 μg pU6-gRNA plasmid with a Gene Pulser XCell (BioRAD) in PBS using previously optimized conditions (Ousterout, O. G., et al. Mol. Ther. 2015, 23, 523-532). Cells were incubated for 72 hours, and genomic DNA was isolated with a DNeasy kit (Qiagen). Indels were identified by PCR of the region of interest (Surveyor Primers provided in TABLE 2) performed using the Invitrogen AccuPrime High Fidelity PCR kit, following by incubation with the Surveyor Nuclease and electrophoresed on TBE gels (Life Technologies) as previously described (Nelson, C. E., et al. Science 2016, 351, 403-407; Guschin, D. Y., et al. Methods Mol. Biol. 2010, 649, 247-256).

TABLE 1 SaCas9 human DMD intron 51 target sequences. Spacer Sequence (Sequence the gRNA targets and binds) PAM gRNA gScbl GCACTACCAGAGCTAACTCA NNGRRT GCACUACCAGAGCUAACUCA (SEQ ID NO: 87) (SEQ ID (SEQ ID NO: 88) NO: 9) g1 CTTTACTTTGTATTATGTAAA AGGAAT CUUUACUUUGUAUUAUGUAAA (SEQ ID NO: 29) (SEQ ID (SEQ ID NO: 64) NO: 89) g2 TTTGAAATATTTTTGATATCT AAGAAT UUUGAAAUAUUUUUGAUAUCU (SEQ ID NO: 30) (SEQ ID (SEQ ID NO: 65) NO: 90) g3 TTTAAGTAATCCGAGGTACTC CGGAAT UUUAAGUAAUCCGAGGUACUC (SEQ ID NO: 31) (SEQ ID (SEQ ID NO: 66) NO: 91) g4 TTTAAATACATTGTCGTAATT CAGAAT UUUAAAUACAUUGUCGUAAUU (SEQ ID NO: 32) (SEQ ID (SEQ ID NO: 67) NO: 92) g5 TACCTTAATTTTGACGTCACA CAGAAT UACCUUAAUUUUGACGUCACA (SEQ ID NO: 33) (SEQ ID (SEQ ID NO: 68) NO: 92) g6 ATTTGACAGGTGAGAAATCTC AGGGGT AUUUGACAGGUGAGAAAUCUC (SEQ ID NO: 34) (SEQ ID (SEQ ID NO: 69) NO: 93) g7 TCATTTATAATACAGGGGAAT AGGAAT UCAUUUAUAAUACAGGGGAAU (SEQ ID NO: 35) (SEQ ID (SEQ ID NO: 70) NO: 89) g8 TTAAAGTCATTTATAATACAG GGGAAT UUAAAGUCAUUUAUAAUACAG (SEQ ID NO: 36) (SEQ ID (SEQ ID NO: 71) NO: 94) g9 AAATAGACACTGAAGAAAGGG AAGAAT AAAUAGACACUGAAGAAAGGG (SEQ ID NO: 37) (SEQ ID (SEQ ID NO: 72) NO: 90) g10 CCCCAATTAAAATAAAATTTA CTGAGT CCCCAAUUAAAAUAAAAUUUA (SEQ ID NO: 38) (SEQ ID (SEQ ID NO: 73) NO: 95) g11 TAAGTAATCCGAGGTACTC CGGAAT UAAGUAAUCCGAGGUACUC (g3) (SEQ ID NO: 39) (SEQ ID (SEQ ID NO: 74) NO: 91) g12 TTAAGTAATCCGAGGTACTC CGGAAT UUAAGUAAUCCGAGGUACUC (g3) (SEQ ID NO: 40) (SEQ ID (SEQ ID NO: 75) NO: 91) g13 GTTTAAGTAATCCGAGGTACT CGGAAT GUUUAAGUAAUCCGAGGUAC (g3) C (SEQ ID UC (SEQ ID NO: 41) NO: 91) (SEQ ID NO: 76) g14 GGTTTAAGTAATCCGAGGTAC CGGAAT GGUUUAAGUAAUCCGAGGUA (g3) TC (SEQ ID CUC (SEQ ID NO: 42) NO: 91) (SEQ ID NO: 77) g15 TTGACAGGTGAGAAATCTC AGGGGT UUGACAGGUGAGAAAUCUC (g6) (SEQ ID NO: 43) (SEQ ID (SEQ ID NO: 78) NO: 93) g16 TTTGACAGGTGAGAAATCTC AGGGGT UUUGACAGGUGAGAAAUCUC (g6) (SEQ ID NO: 44) (SEQ ID (SEQ ID NO: 79) NO: 93) g17 CATTTGACAGGTGAGAAATCT AGGGGT CAUUUGACAGGUGAGAAAUCU (g6) C (SEQ ID C (SEQ ID NO: 45) NO: 93) (SEQ ID NO: 80) g18 TCATTTGACAGGTGAGAAATC AGGGGT UCAUUUGACAGGUGAGAAAUC (g6) TC (SEQ ID UC (SEQ ID NO: 46) NO: 93) (SEQ ID NO: 81) g19 ATTTATAATACAGGGGAAT AGGAAT AUUUAUAAUACAGGGGAAU (g7) (SEQ ID NO: 47) (SEQ ID (SEQ ID NO: 82) NO: 89) g20 CATTTATAATACAGGGGAAT AGGAAT CAUUUAUAAUACAGGGGAAU (g7) (SEQ ID NO: 48) (SEQ ID (SEQ ID NO: 83) NO: 89) g21 GTCATTTATAATACAGGGGAA AGGAAT GUCAUUUAUAAUACAGGGGAA (g7) T (SEQ ID U (SEQ ID NO: 49) NO: 89) (SEQ ID NO: 84) g22 AGTCATTTATAATACAGGGGA AGGAAT AGUCAUUUAUAAUACAGGGGA (g7) AT (SEQ ID AU (SEQ ID NO: 50) NO: 89) (SEQ ID NO: 85) g23 GCACTACCAGAGCTAACTCA GCACUACCAGAGCUAACUCA (SEQ ID NO: 51) (SEQ ID NO: 86)

TABLE 2 Primer sequences. Description Forward Primer (5′-3′) Surveyor Fwd: CTGATGCTCTCCAAACTTGCC (SEQ ID NO: 98) (g1, g5, g6) Rev: TGCTTTGTGTGTCCCATGCT (SEQ ID NO: 99) Surveyor Fwd: ATACCTCTGAGATTGTGGTCCT (SEQ ID NO: 100) (g2, g3, g4) Rev: TGGGCAGCGGTAATGAGTTC (SEQ ID NO: 101) Surveyor Fwd: TTACTGAGTTTTAGAACCAGAGCTA (SEQ ID NO: 102) (g7, g8) Rev: AGGGTTCTTCAGCGTTGTGT (SEQ ID NO: 103) Surveyor Fwd: AGCAGGAGTCAAAGTACAGAGT (SEQ ID NO: 104) (g9, g10) Rev: TCCGGAGTACCTCGGATTAC (SEQ ID NO: 105) gDNA integration Fwd: TTACTGAGTTTTAGAACCAGAGCTA (SEQ ID NO: 106) PCR Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 107) CDNA integration Fwd: CTGACCACTATTGGAGCCTCTC (SEQ ID NO: 108) PCR Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 109) 3′ RACE GSP GTAGTCGTTTAAACCGCTGATCAGCCTCG (SEQ ID NO: 110) ddPCR - Corrected Fwd: GCTTTCTCTGCTTGATCAAG (SEQ ID NO: 111) (Ex51-Ex52 junction) Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 112) Probe: GCAACAATGCAGGATTTG (SEQ ID NO: 113) ddPCR - Unedited Fwd: GCTTTCTCTGCTTGATCAAG (SEQ ID NO: 114) (Ex51-Ex53 junction) Rev: CGGTTCTGAAGGTGTTCTTGTA (SEQ ID NO: 115) Probe: AGCAGAAGTTGAAAG (SEQ ID NO: 116) ddPCR - Fwd: GATGAGCTGGACCTCAAGCT (SEQ ID NO: 117) Normalization Rev: GTGGCTCACGTTCTCTTTCA (SEQ ID NO: 118) (Ex59-Ex60 junction) Probe: CGAGAAAGTCAAGGCACT (SEQ ID NO: 119) Tn5-Top CAAGCAGAAGACGGCATACGAGATNNNNNNNNNNGTCTCGTGGG CTCGGAGATGTGTATAAGAGACAG (SEQ ID NO: 120) Tn5-Bottom [Phos]CTGTCTCTTATACACATCT (SEQ ID NO: 121) Tn5-GSP (g7) AAGCAGTGGTATCAACGCAGAGTACCAGAGAAAATAGACACTGA AGAAAGGG (SEQ ID NO: 122) Tn5-GSP (g12) AAGCAGTGGTATCAACGCAGAGTACCCTTAATTTTGACGTCACAC AGAATG (SEQ ID NO: 123) Tn5-Universal CAAGCAGAAGACGGCATACGAGAT (SEQ ID NO: 124) Tn5-BC, [i5 barcode] AATGATACGGCGACCACCGAGATCTACAC[NNNNNN]CGGAAGCA GTGGTATCAACGCAGAGTAC (SEQ ID NO: 125) Tn5-Read1 CGGAAGCAGTGGTATCAACGCAGAGTAC (SEQ ID NO: 126) (Miseq/Novaseq) Tn5-Index1 GTACTCTGCGTTGATACCACTGCTTCCG (SEQ ID NO: 127) (Novaseq)

Animals. All experiments involving animals were conducted with strict adherence to the guidelines for the care and use of laboratory animals of the National Institutes of Health (NIH). All experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at Duke University. The hDMD/mdx mouse (t Hoen, P. A., et al. J. Biol. Chem. 2008, 283, 5899-5907) was kindly provided by Leiden University Medical Center. The generation of the hDMDΔ52/mdx mouse was completed by the Duke Transgenic Mouse Facility. Briefly, B6SJLF1/J donor females were superovulated by intraperitoneal injection of 5IU PMSG on day one and 5IU HCG on day three, followed by mating with fertile hDMD/mdx males. On day four, embryos were harvested and injected with mRNA encoding S. pyogenes Cas9 and gRNAs targeting human intron 51 (CTCTGATAACCCAGCTGTGTGTT, SEQ ID NO: 96) and human intron 52 (CTAGACCATTTCCCACCAGTTCT; SEQ ID NO: 97). Injected embryos were implanted into pseudo-pregnant CD1 female mice. Genomic DNA was extracted from ear punches of chimeric pups using the DNeasy Blood and Tissue Kit (Qiagen) and screened for presence or deletion of exon 52. Mice with loss of exon 52 were bred with mdx mice. The resulting male hDMDΔ52/mdx (het;hemi) mice were used for experiments.

In Vitro AAV Transductions. Primary myoblasts were isolated from the tibialis anterior (TA) and gastrocnemius muscles of hDMDΔ52/mdx mice, as previously described (Springer, M. L., Rando, T. A. & Blau, H. M. Gene delivery to muscle. Curr. Protoc. Hum. Genet. Chapter 13, Unit13.14), and maintained in F10 media (Invitrogen) supplemented with 20% FBS, 5 ng/mL bFGF, and 1% P/S. Cells were grown on plates coated with bovine type I collagen (Sigma) and incubated at 37° C. with 5% CO₂. For transductions, cells were plated for 1.5 hours then AAV2-SaCas9 and AAV2-gRNA-donor vectors were combined, added to the plates at an MOI of 1×10⁶ total vectors per cell. Cells were immediately spun at 3000×g for 5 min and returned to the incubator. Once cells reached 70% confluency, the media was changed to DMEM supplemented with 5% horse serum and 1% P/S and replaced every 2 days for differentiation into myofibers. Cells were differentiated for 10 days and processed for analysis of genomic DNA, total RNA, and protein as described.

Genomic DNA and RNA Analysis from Primary hDMDΔ52/mdx Myoblasts. Genomic DNA was isolated using the DNeasy kit (Qiagen) according to the manufacturer's protocol. Total RNA was isolated using QIAshredder and RNeasy Plus kits (Qiagen). First-strand cDNA synthesis was performed using 500 ng total RNA per sample using the SuperScript VILO Reverse Transcription Kit (Invitrogen) and incubated at 25° C. for 10 min, 42° C. for 2 hours, and 85° C. for 5 min. Donor integration was detected by PCR (Primers provided in TABLE 2) using the Invitrogen AccuPrime High Fidelity PCR kit according to the manufacturer's protocol and electrophoresed on 1% agarose gels. 3′ RACE was carried out on RNA samples using the SMARTer RACE 5′/3′ kit (Takara) for cDNA synthesis and primary PCR (Primers provided in TABLE 2) using Program 1 according to the manufacturer's instructions.

In Vivo AAV Administration. Adult 6-8 week-old mice were administered AAV by intramuscular injection into the tibialis anterior muscle with 40 μL PBS or AAV vector per mouse. For the donor comparative study, 1.56e12 total vg was administered to 1:1 treatment groups (7.81e11 AAV-Cas9 and 7.81e11 AAV-donor) and 2.13e12 total vg was administered to 1:5 treatment groups (3.55e11 AAV-Cas9 and 1.77e12 AAV-donor). For the gRNA comparative study, 8.64e11 total vg was administered to the 1:1 treatment groups (4.32e11 AAV-Cas9 and 4.32e11 AAV-donor) and 7.00e11 total vg was administered to the 1:5 treatment groups (1.17e11 AAV-Cas9 and 5.83e11 AAV-donor). Two-day-old (P2) neonatal mice were administered AAV by intravenous injection through the facial vein (Gombash Lampe, et al. J. Vis. Exp. 2014, e52037) with 40 μL AAV vector per mouse. For the 1:1 treatment groups, 8.64e11 total vg was administered (4.32e11 AAV-Cas9 and 4.32e11 AAV-donor) and for the 1:5 treatment groups, 7.00e11 total vg was administered (1.17e11 AAV-Cas9 and 5.83e11 AAV-donor). At set time points, mice were euthanized and skeletal muscle, cardiac muscle, and serum was collected.

Droplet Digital PCR. Quantitative ddPCR was performed on cDNA and gDNA samples using the WX200 Droplet Digital PCR system according to the manufacturer's instructions. To quantify corrected transcript levels, RNA was extracted from mouse tissues using the Qiagen Universal kit. Subsequently, First-strand cDNA synthesis was performed using 500 ng total RNA per sample as stated above. Corrected hDMD transcripts containing exon 52 were detected using the QX200 ddPCR Supermix for Probes without dUTP (BioRad) and Taqman assays with probes (TABLE 2) designed to bind to the human dystrophin Ex51-52 junction (corrected, ThermoFisher custom assay ID: AP2XDZ9), human dystrophin Ex51-53 junction (unedited, ThermoFisher custom assay ID: AP327K6), and human dystrophin Ex59-60 (input normalization, ThermoFisher custom assay ID: AP47Z63). Quantification was determined based on the number of positive droplets in each reaction using QuantaSoft Analysis software (BioRad). cDNA input for corrected or unedited transcript levels was normalized by dividing the number of Ex51-52 or Ex51-53 of positive droplets, respectively, by the number of positive Ex59-60 droplets in each reaction. The percentage of corrected transcripts was calculated as (Normalized Ex51-52)/[(Normalized Ex51-52)+(Normalized Ex51-53)]×100. For vector genome quantification, gDNA was extracted from mouse tissues using the Qiagen DNeasy kit and digested with HindIII-HF at 37° C. for 1 hour. Episomes were detected using the QX200 ddPCR Supermix for Probes without dUTP (BioRad) and BioRad assays with probes (TABLE 2) designed to bind SaCas9 (AAV-SaCas9, BioRad unique assay ID: dCNS159380965), U6 (AAV-gRNA-donor, BioRad unique assay ID: dCNS116676529), and mouse EEF2 (input normalization, BioRad unique assay ID: dMmuCNS781688813). Quantification was determined based on the number of positive droplets in each reaction using QuantaSoft Analysis software. Episome quantification was calculated as viral genomes per diploid genome (vg/dg) by dividing the number of SaCas9 or U6 positive droplets by the number of mouse EEF2 positive droplets in the corresponding reaction.

Transposon-mediated target enrichment and sequencing. Tn5 transposase protein was expressed and purified as previously described (Picelli, S., et al. Genome Res. 2014, 24, 2033-2040). Tagmentation of genomic DNA was completed as previously described (Giannoukos, G., et al. BMC Genomics 2018, 19, 212), with the following modifications to include unique molecular indexes (UMIs). For RNA transcript analysis, first-strand cDNA synthesis was performed using 500 ng total RNA per sample as stated above. Second-strand synthesis was performed using Kenow fragment DNA polymerase (NEB) and purified using Ampure beads (Beckman Coulter) at 1.8×. All primer sequences are provided in TABLE 2. In brief, the linker oligonucleotides (Tn5-Top contains Illumina i7 adapter sequence and 10 nucleotide UMI, Tn5-Bottom contains Tn5-ME sequence) were annealed and assembled on Tn5. Genomic DNA was quantified using NanoDrop (ThermoFisher) and second-strand products were quantified using Qubit Fluorometric Quantification (ThermoFisher). Tagmentation of 200 ng genomic DNA or second-strand products was performed using a 1:40 dilution of assembled Tn5 and purified using DNA Clean and Concentrator-5 columns or 96-well kits (Zymo). To enrich the targeted sequence, first round PCR using a genome specific primer (Tn5-GSP, contains custom adapter) was used with a reverse primer (Tn5-Universal) specific for the i7 adapter sequence inserted by the transposon for 25 cycles. Amplicons were purified with Ampure beads at 1.8×. Second round PCR using a barcode primer (Tn5-BC) specific for the custom adapter sequence was used to add 6-nucleotide experimental barcodes and the Illumina i5 adapter was used with the Tn5-Universal reverse primer for 15 cycles. Amplicons were gel-purified, followed by purification with Ampure beads at 0.6× to select for fragment sizes greater than 250 bp. Sequencing was conducted on an Illumina Miseq using 250/50-cycle paired-end reads with a custom read 1 primer (Tn5-Read1) or on an Illumina Novaseq v1.5 using 300-cycle single-end reads with a custom read 1 primer (Tn5-Read1) and custom index 1 primer (Tn5-Index1). The Tn5-based method is expected to reduce PCR-related bias from amplicon size; however, some bias may remain from the transposition selectivity (Giannoukos, G., et al. BMC Genomics 2018, 19, 212). Briefly, the analysis steps are as follows: Demultiplex. Demultiplex fastq files using the list of barcodes for each sample. Trim. Remove the 3′ adapters and low-quality bases using Trimmomatic. Alignment and deduplication. Using bwa-mem, align the reads to reference genomes (gDNA aligned to mouse genome (GRCm38)+human DMD; cDNA aligned to human dystrophin cDNA) with PCR duplicates marked using Picard MarkDuplicates and removed. Alignment to reference bin sequences. Build reference amplicons to align to the targeted locus and expected edits. To remove reads that are due to false priming, filter out reads that do not contain the 20 bases directly adjacent to the GSP expected sequence. To remove reads that do not extend far enough past the edit site, filter out reads that are shorter than the required minimum length for binning. Align on-site deduplicated reads to reference amplicons using bwa-mem. Identify reads where there is an indel ±15 bp at the expected cute site or junction. The number of distinct UMIs were counted for each edit.

Western blot. Protein was isolated from muscle tissues by disruption with a BioMasher II Micro Tissue Homogenizer (VWR) in RIPA buffer (Sigma) with a protease inhibitor cocktail (Roche) and incubated for 30 minutes on ice with intermittent vortexing. Samples were spun at 16,000×g at 4° C. for 30 minutes and supernatant was collected. Total protein was quantified using the BCA Protein assay kit (Pierce) according to the manufacturer's protocol and measured on a BioTek Synergy 2 Multi-Mode Microplate Reader. S ample was mixed with NuPAGE loading buffer (Invitrogen) and 5% β-mercaptoethanol, and 3.125 μg of hDMD/mdx protein or 25 μg of all other protein samples was heated at 100° C. for 10 min. Samples were loaded into 4-12% NuPAGE Bis-Tris gels (Invitrogen) with MES buffer (Invitrogen) and electrophoresed for 45 min at 200V on ice. Protein was transferred to nitrocellulose membranes for 90 minutes in 1× tris-glycine transfer buffer with 0.01% SDS at 4° C. at 400 mA. The blot was blocked in 5% milk-TBST (50 mM Tris, 150 mM NaCl and 0.1% Tween-20) at 4° C. overnight. Blots were cut and incubated with anti-MANDYS106 (1:50 dilution, Millipore clone 2C6), anti-HA (1:1000 dilution, Biolegend clone 16B12, or anti-GAPDH (1:5000 dilution, Cell Signaling clone 14C10) in 5% milk-TBST at room temperature for 1 hour. Blots were then washed in TBS-T and incubated with goat anti-mouse-conjugated horseradish peroxidase (1:2500 dilution, Sigma) or goat anti-rabbit-conjugated horseradish peroxidase (1:2500 dilution, Sigma) in 5% milk-TBS-T at room temperature for 1 hour. Blots were washed in TBST then visualized using Western-C ECL substrate (Bio-Rad) on a ChemiDoc XRS+ System (Bio-Rad).

Histological analysis. Muscles were dissected and embedded in OCT or flash-frozen using liquid nitrogen-cooled isopentane. Subsequently, 10 μm sections were cut onto pretreated histological slides using a cryostat (Leica). Slides were washed in PBS and blocked in PBS supplemented with 5% BSA, and 0.1% Triton X-100. Slides were stained with mouse anti-MANDYS106 (1:200 dilution, Millipore clone 2C6) and rabbit anti-Laminin (1:300 dilution, Sigma L9393) in blocking buffer at room temperature for 1 hour. Slides were washed 3× with PBS for 5 minutes and goat anti-mouse IgG2a, Alexa Fluor 594 (1:500 dilution, ThermoFisher A-21135) or goat anti-rabbit IgG (H+L), Alexa Fluor 488 (1:500 dilution, ThermoFisher A-11034) was applied with DAPI (1:1000 dilution) at room temperature for 1 hour. Slides were washed and mounted with ProLong Gold Antifade Mountant (Invitrogen) and imaged with a Zeiss AxioObserve 7 microscope. Total fibers (anti-Laminin) were counted using the analyze particles function on ImageJ (Schindelin, J., et al. Nat. Methods 2012, 9, 676-682) and human dystrophin-positive fibers (anti-MANDYS106) were manually counted from a series of 5 randomized images for each sample. Percent dystrophin-positive fibers were calculated as dystrophin-positive fibers divided by the total fibers for each image. P-values were calculated by nested global one-way ANOVA with Tukey post hoc multiple comparisons tests.

Off-target analysis. CIRCLE-seq libraries (Tsai, S. Q., et al. Nat. Methods 2017, 14, 607-614) were generated as previously described (Kocak, D. D., et al. Nat. Biotechnol 2019, 37, 657-666). Approximately 50-100 μg of HEK293T gDNA was used to generate circles for each reaction. Using a Diagenode Bioruptor XL sonicator at 4° C., gDNA was sonicated to an average size of approximately 50 bp, with a visible range of 200-1000 bp, as determined by agarose gel electrophoresis. The enzymatic procedure to generate circles was carried out as previously described (Tsai, S. Q., et al. Nat. Methods 2017, 14, 607-614). For the in vitro digest of the circles, gRNAs were synthesized from IDT and SaCas9 was purchased from Applied Biological Materials. Library production was carried out as previously described for CHANGE-seq (Lazzarotto, C. R., et al. Nat. Biotechnol. 2020, 38, 1317-1327). Libraries were quantified by the qPCR-based KAPA Library Quantification Kit (KAPA Biosystems), pooled, and sequenced with 150-bp paired-end reads on an Illumina NextSeq instrument. Read counts were obtained using previously described methods and software for CHANGE-seq (Lazzarotto, C. R., et al. Nat. Biotechnol. 2020, 38, 1317-1327). The following parameters were used for running the analysis pipeline: read threshold of 4, window size of 3, mapq threshold of 50, start threshold of 1, gap threshold of 3, mismatch threshold of 6, and PAM of NNGRRN (SEQ ID NO: 8; Ran, F. A., et al. Nature 2015, 520, 186-191).

Creatine kinase assay. Serum creatine kinase was measured using a Liquid Creatine Kinase Reagent set (Pointe Scientific) following the manufacturer's instructions. In brief, 5 μL of serum was diluted in 45 μL sterile PBS and incubated with reagent for 2 min at 37° C. followed by absorbance measurements taken every minute three readings using a nanodrop spectrophotometer set for 340 nm readings. Calculations for total creatine kinase in U/L were made according to the manufacturer's instructions.

Statistical analysis. All data was analyzed with four to six biological replicates and presented as mean±SEM. All p-values were calculated by global one-way ANOVA with Tukey post hoc tests (α=0.05).

Example 2 Correction Strategy for Humanized Mouse Model of DMD

The hDMD/mdx mouse lacks mouse dystrophin due to the hallmark mdx mutation but produces human dystrophin from the full-length human DMD (hDMD) gene on mouse chromosome 5. These mice can be used to generate humanized DMD mouse models by removing hDMD exons known to be missing in patient populations, and thus eliminating all dystrophin expression. Importantly, these humanized models can be used to test therapeutic strategies because human dystrophin restoration can functionally compensate for the lack of mouse dystrophin. To study various gene editing therapeutic strategies, a hDMDΔ52/mdx mouse model was generated by delivering Streptococcus pyogenes Cas9 (SpCas9) and gRNAs to hDMD/mdx zygotes for targeted exon 52 deletion from the hDMD gene. Deletion of exon 52 results in an out-of-frame mutation (FIG. 3A) that creates a premature stop codon and subsequent loss of dystrophin expression. To restore full-length dystrophin expression, a HITI-based approach was developed to insert exon 52 at its corresponding position in the hDMD gene in this humanized hDMDΔ52/mdx mouse model. This dual AAV vector approach includes one AAV vector that encodes a Staphyloccocus aureus Cas9 (SaCas9) (Ran, F. A., et al. Nature 2015, 520, 186-191) expression cassette and a second AAV vector that encodes a gRNA expression cassette with the exon 52 donor sequence (Ex52) flanked by the same gRNA target site found in intron 51 of the hDMD gene. Following co-delivery of both AAV vectors, Cas9 and the gRNA was expressed and created a DSB at the genomic target site, as well as liberated the Ex52 donor sequence from the AAV vector so that following NHEJ-based repair, the exon 52 sequence integrated into the target site and restore a full-length dystrophin gene. The gRNA target sites were in opposite orientation in the genomic DNA and AAV vector so that correct donor integration disrupted the gRNA target sequence and prohibited further Cas9-based editing (FIG. 3A).

Example 3 Screening and Validation of HITI-Mediated Integration

The specificity of DNA cleavage by the CRISPR-Cas9 system is critical to ensuring the safety and efficacy of this approach. To minimize potential off-target effects, bioinformatic analysis was used to design gRNAs with limited predicted off-target sites in murine and human genomes. A panel of SaCas9 gRNAs targeting intron 51 (FIG. 8A, TABLE 1) was screened to identify targets with high specificity and activity, initially using the Surveyor assay following plasmid transfection of HEK293T cells (FIG. 8B). SaCas9 activity can vary across a range of spacer lengths, therefore 19-23 nt spacers of the top gRNAs were generated and individually screened for activity by Surveyor assay, following plasmid electroporation into DMD patient myoblasts (FIG. 8C). The individual gRNA sequences with the highest activity levels and fewest predicted off-target sites (g12 and g7), along with a scrambled non-target control gRNA (gScbI), were cloned into AAV vector plasmids for gRNA expression and the corresponding spacer and PAM target sequences were included flanking the donor sequence.

To validate targeted integration of the Ex52 donor sequence, primary myoblasts were isolated from hDMDΔ52/mdx skeletal muscle (FIG. 3B). Following electroporation of AAV plasmids, targeted Ex52 integration in genomic DNA (gDNA) was confirmed by Sanger sequencing of the PCR amplified genome-donor junction for g12-Ex52 and g7-Ex52 treated hDMDΔ52/mdx primary myoblasts, but not gScbI-treated cells (FIG. 8D). To validate AAV-mediated targeted integration and subsequent correction of dystrophin transcripts and protein restoration, primary myoblasts were transduced with AAV2 and then cultured the cells in differentiation conditions to upregulate dystrophin expression (FIG. 3B). In addition to delivering both AAV2 constructs at equal doses (1:1), delivery of 5× more AAV-donor than AAV-Cas9 (1:5) was also tested. Total volume of AAV preps remained consistent for 1:1 and 1:5 treatment groups, resulting in delivery of more AAV-Cas9 viral genomes for the 1:1 treatment group. Using both delivery ratios, targeted Ex52 integration was confirmed in gDNA by PCR amplification of the genome-donor junction (FIG. 3C). The presence of a larger amplicon was detected, which was confirmed to be intact AAV-donor integration by Sanger sequencing (data not shown). Additionally, the presence of Ex52 was observed in dystrophin cDNA following PCR amplification (FIG. 3D) and resulted in dystrophin protein restoration (FIG. 3E). The higher Cas9 expression observed in 1:1 treated cells correlated with the higher AAV-Cas9 viral dose. These results confirm activity of the AAV-Cas9-based strategy for targeted Ex52 integration and full-length dystrophin protein restoration.

Example 4 AAV-Cas9 Exon 52 Integration Restores Full-Length Dystrophin In Vivo

AAV9 was used for delivery of the CRISPR-Cas system to hDMDΔ52/mdx mouse skeletal and cardiac muscle. Following co-injection of the two AAV vectors into the tibialis anterior (TA) muscle of adult hDMDΔ52/mdx male mice (FIG. 4A), local AAV vector delivery at comparable levels was confirmed for both g12 and g7 vectors by digital droplet PCR (ddPCR) of DNA vector genomes (FIG. 4B). Targeted Ex52 integration was confirmed in gDNA from TA tissue by PCR amplification of the genome-donor junction using both AAV delivery ratios and intact AAV-donor integration (FIG. 4C). To quantify editing activity and comprehensively map possible genome editing outcomes with an unbiased approach, Tn5-transposon-based library preparation methods (Nelson, C. E., et al. Nat. Med. 2019; Giannoukos, G., et al. BMC Genomics 2018, 19, 212) were adapted and included unique molecular identifiers (UMI) to remove PCR duplicates for increased accuracy of quantifying rare events. The Tn5-based method eliminated PCR biases associated with target specificity and amplicon length by using a single genome-specific primer (GSP) adjacent to a gRNA cut site in combination with a transposon-specific primer for the Tn5-integrated DNA tag. In addition to quantifying donor integrations in the correct orientation, genome editing events were measured that included indels, donor inversion integrations, and AAV-ITR integrations (FIG. 4D). Higher correction and total genomic editing events were measured in g7 treated mice (FIG. 4E, FIG. 4F, FIG. 9A, and FIG. 9B), however indel and AAV integration edits were also observed in g12 treated mice (FIG. 4E, FIG. 9A, and FIG. 9B). Although corrected genomic reads were not detected in g12 treated mice, the presence of exon 52 was observed in corrected dystrophin cDNA following PCR amplification (FIG. 4G) and quantified by ddPCR (FIG. 4H) for all treatment groups. Full-length dystrophin restoration was confirmed by Western blot of whole TA tissue lysates (FIG. 4I) and dystrophin positive fibers were quantified by immunofluorescence (IF) (FIG. 4J). These results confirmed in vivo activity of the AAV-Cas9-based strategy for targeted Ex52 integration and full-length dystrophin protein restoration following local injection in hDMDΔ52/mdx mouse skeletal muscle.

Assessing CRISPR-Cas targeting specificity may be important for pre-clinical development. Collectively, greater genome editing activity and subsequent dystrophin restoration was measured for g7-treated mice (FIG. 3A-3F), thus the specificity analyses were focused on g7. To empirically determine the top g7 off-target sites in the human genome with an unbiased genome-wide assay, high-throughput genome-wide editing quantification was performed (Tsai, S. Q., et al. Nat. Methods 2017, 14, 607-614; Lazzarotto, C. R., et al. Nat. Biotechnol. 2020, 38, 1317-1327) (FIG. 10 ). These analyses identified 6 potential off-target sites with editing activity≤1.07% of on-target gDNA editing, confirming high specificity of this g7 gRNA. For the remainder of the work, g7-targeted full-length dystrophin restoration strategies were focused on.

Example 5 In Vitro Validation of AAV-Cas9 Superexon Strategy for Full-Length Dystrophin Restoration

The g7-Ex52 integration approach can correct full-length dystrophin for Δ52 DMD patients and restore the proper reading frame to produce a truncated dystrophin protein for Δ52-58, Δ52-61, and Δ52-76 patient mutations. To expand the full-length dystrophin correction strategy to treat any genetic mutation downstream of exon 51, an AAV-superexon donor vector was engineered. This superexon encoded the complete dystrophin cDNA coding sequence downstream of exon 51, including exons 52 through 79. Additionally, the stop codon was replaced with a 3× stop to ensure translation termination in all reading frames, included the SV40 polyA sequence, and flanked the donor cassette with the previously validated g7 target sites (FIG. 5A). Targeted integration of this g7-superexon construct could correct full-length dystrophin in >20% of all DMD patients.

To validate superexon integration and subsequent correction of dystrophin transcripts and protein restoration, primary myoblasts were transduced with AAV2 at 1:1 and 1:5 vector ratios, then the cells were cultured in differentiation conditions to upregulate dystrophin expression (FIG. 5B). Targeted integration was confirmed in gDNA by PCR amplification of the genome-donor junction for all treated samples, in addition to detection of intact AAV-donor integration (FIG. 5C). The presence of exon 52 from both donors was observed at comparable levels in dystrophin cDNA following PCR amplification (FIG. 5D). For wild-type dystrophin transcripts, almost 2.7 kb of untranslated region (3′ UTR) was included in exon 79 following the stop codon. In the superexon donor, this sequence was replaced with a shortened polyA signal due to the packaging size restrictions of AAV (˜4.7kb). To characterize this engineered 3′ UTR, 3′ RACE was performed using cDNA of AAV-transduced cells and superexon-corrected dystrophin transcripts were amplified using a GSP that recognizes the engineered 3× stop (FIG. 5E). Following Sanger sequencing, addition of a polyA tail was observed within the SV40 polyA signal sequence. Next, it was confirmed that superexon-corrected dystrophin transcripts resulted in dystrophin protein restoration (FIG. 5F). These results confirmed activity of the targeted AAV-Cas9-based Ex52-79 superexon integration strategy for full-length dystrophin protein restoration.

Example 6 AAV-Cas9 Superexon Strategy Restores Full-Length Dystrophin in Skeletal Muscle and Cardiac Muscle

To test the Superexon strategy in vivo, the AAV9 constructs were co-injected at a ratio of 1:1 and 1:5 into the TA muscle of adult hDMDΔ52/mdx male mice (FIG. 6A). A scrambled non-target gRNA donor (gScbI-Ex52) was included as an additional control. At 8 weeks post-injection, equivalent AAV vector genome levels between treatment groups were measured by ddPCR (FIG. 6B). Targeted editing activity was quantified using Tn5-based library preparation and analysis methods with the highest editing levels in the 1:5 treated mice. The lower g7-Ex52 editing levels observed in this donor comparative study (FIG. 6C and FIG. 11A-11B), in contrast to the previous gRNA comparative study (FIG. 4E and FIG. 9A-9B), was likely due to lower AAV transduction in the TA as demonstrated by differences in vector genome quantification (FIG. 4B and FIG. 6B). Although corrected gDNA levels were not detected above background by Tn5 analysis, an increase in the percent of corrected transcripts was observed for all treatment groups (FIG. 6D). Additionally, full-length dystrophin expression was observed by Western blot (FIG. 6E) and IF (FIG. 6F) and quantification of dystrophin positive fibers resulted in a significant increase for g7-Ex52 treated mice compared to the scrambled non-targeted donor control. These results confirmed in vivo activity of the AAV-Cas9-based strategy for targeted superexon integration and full-length dystrophin protein restoration following local injection in hDMDΔ52/mdx mouse skeletal muscle.

Next, the corrective therapeutic potential of these integration strategies was evaluated following systemic delivery. For transduction of cardiac and skeletal muscle, the AAV9 constructs were co-delivered at a ratio of 1:1 and 1:5 by facial vein injection of P2 neonate hDMDΔ52/mdx male mice (FIG. 7A). At 8 weeks post-injection, vector genome quantification by ddPCR revealed higher transduction levels in cardiac tissue than skeletal (diaphragm and TA) tissues (FIG. 7B), suggesting the potential for higher editing activity in hearts of treated mice. Indeed, Tn5-based quantification revealed higher editing for all quantified outcomes in the heart gDNA compared to diaphragm and TA, with the highest on-target correction in hearts of g7-Superexon treatment groups (FIG. 7C and FIG. 12A-12B). Higher levels of corrected dystrophin transcripts were observed in hearts of g7-Superexon treatment groups with mice achieving >25% corrected transcripts (FIG. 7D). The ddPCR-based transcript quantification was limited to detection of unedited (Ex51-Ex53 junction) and corrected (Ex51-Ex52 junction) cDNA molecules. For additional heart transcript characterization, putative aberrant splicing events were measured that included inversion donor integrations, splicing with the SaCas9 coding sequence, circular RNA formation (exons 1-51), multi-exon skipping (exons 53-79), and alternative splicing with downstream intronic sequences (introns 51-53) (FIG. 7E). Higher levels of editing were measured by ddPCR than Tn5-based deep sequencing strategies. Lower deep sequencing editing percentages may be attributed by larger denominators generated from measuring unintended gene editing outcomes. For cDNA analysis, the high-throughput deep sequencing characterization revealed considerable aberrant splicing with the SaCas9 coding sequence in two treated mice (FIG. 13A). Upon further investigation, genomic integration of aligned sequences in corresponding genomic mouse samples was confirmed (FIG. 13B). Transcript isoforms that contain partial AAV genomes, including partial SaCas9 coding sequences, have an unknown biological effect and could be investigated in future studies. In heart tissue, full-length dystrophin restoration was confirmed by Western blot (FIG. 7F) and dystrophin-positive cells were detected in all treated mice (FIG. 7G and FIG. 14 ). A significant increase in dystrophin-positive cells was observed for g7-superexon (1:1) treated mice compared to the scrambled non-targeted gRNA donor control, with almost 50% of dystrophin-positive cells observed for one mouse. Serum creatine kinase levels, a marker of muscle degeneration, were significantly higher for control hDMDΔ52/mdx mice compared to hDMD/mdx mice, suggestive of a diseased DMD phenotype (FIG. 7H). Additionally, serum creatine kinase levels were reduced in hDMDΔ52/mdx mice after all systemic treatments, demonstrating protection from muscle damage by the restored full-length dystrophin protein.

Example 7 Discussion

DMD gene therapy strategies have been explored for nearly 30 years, however strategies to correct full-length dystrophin are lacking. In this study, use of targeted HITI-mediated transgene insertion was demonstrated for full-length human dystrophin correction and restoration in hDMDΔ52/mdx mice. A dual AAV delivery system was used for generating a Cas9-targeted genomic DSB and delivering donor sequences for NHEJ-mediated integration at the cut site. Here, the therapeutic potential of NHEJ-mediated integration approaches following both local injection and systemic delivery in skeletal and cardiac tissues was demonstrated. Additionally, high-throughput unbiased sequencing was performed to characterize and quantify genomic and transcriptional editing events.

Although downstream consequences of HITI-mediated correction resulted in dystrophin protein restoration, the deep sequencing results demonstrate low genomic correction efficiency. The observation of high dystrophin protein restoration resulting from low genomic editing efficiency is consistent with alternative DMD gene editing approaches. While low levels of dystrophin expression, even less than 4% of normal, can result in potential therapeutic benefit, improving HITI efficiency will aid translation of knock-in gene therapy strategies to clinical applications. The gene editing strategy detailed herein may be similar to other gene transfer strategies in its need for robust delivery to targeted tissues and cells. Methods to improve AAV-mediated tissue-specific transduction and expression, such as AAV capsid evolution and promoter engineering, may improve gene editing activity and therapeutic potential. Additionally, targeted integration in dividing and non-dividing cells may be increased by identification of NHEJ regulators leading to the development of small molecule targets for enhancing HITI-mediated activity. Alternatively, other targeted gene knock-in methods can be explored including microhomology-mediated end-joining (MMEJ), Precise Integration into Target Chromosome (PiTCh), homology-mediated end joining (HMEJ), and intercellular linearized Single homology Arm donor mediated intron-Targeting Integration (SATI). With continued progress in editing efficiency, HITI-mediated transgene knock-in holds great promise for future development of corrective gene therapy strategies.

Pre-clinical gene editing studies may benefit from use of humanized mouse models because they permit testing of therapeutic approaches specifically designed to treat human patients. To apply HITI-based gene therapy strategies to a DMD disease model that recapitulates mutations found in patients, hDMDΔ52/mdx mice were utilized, which contain a gene deletion in the DMD patient mutational hotspot of exons 45-55. Full-length protein restoration was demonstrated following targeted integration of the missing exon 52 coding sequence. To expand this corrective gene therapy approach to a larger patient population (>20%), a superexon encoding the complete human dystrophin cDNA coding sequence downstream of exon 51 was engineered that can correct all patient mutations located after exon 51, and demonstrated full-length protein restoration using this approach. This work is the first demonstration of a targeted gene editing approach to permanently correct full-length dystrophin. This approach will be extended to all patients with mutations within and downstream of the exon 45-55 hotspot (>50% of all patients), for example, with a dual AAV-based system with one AAV that encodes SaCas9 and a gRNA targeting intron 44, and a second donor AAV vector that contains the human dystrophin cDNA coding sequence downstream of exon 44 (exons 45-79). Sequences for gRNAs targeting intron 44 are shown in TABLE 3. Exons 45-79 of the human dystrophin gene may be encoded by a polynucleotide of SEQ ID NO: 154, and an example of a donor sequence for insertion of exons 45-79 is shown in SEQ ID NO: 155.

TABLE 3 Examples of gRNAs targeting intron 44 of human dystrophin gene. DNA encoding gRNA gRNA GGGGCTCCACCCTCACGAGT GGGGCUCCACCCUCACGAGU (SEQ ID NO: 157) (SEQ ID NO: 171) GCACAAAAGTCAAATCGGAA GCACAAAAGUCAAAUCGGAA (SEQ ID NO: 158) (SEQ ID NO: 172) GATTTCAATATAAGATTCGG GAUUUCAAUAUAAGAUUCGG (SEQ ID NO: 159) (SEQ ID NO: 173) GTGAGGGCTCCACCCTCACGA GUGAGGGCUCCACCCUCACGA (SEQ ID NO: 160) (SEQ ID NO: 174) GAAGGATTGAGGGCTCCACCC GAAGGAUUGAGGGCUCCACCC (SEQ ID NO: 161) (SEQ ID NO: 175) GGCTCCACCCTCACGAGTGGG GGCUCCACCCUCACGAGUGGG (SEQ ID NO: 162) (SEQ ID NO: 176) GTGAGGGCTCCACCCTCACGA GUGAGGGCUCCACCCUCACGA (SEQ ID NO: 163) (SEQ ID NO: 177) GGGCTCCACCCTCACGAGT GGGCUCCACCCUCACGAGU (SEQ ID NO: 164) (SEQ ID NO: 178) CACAAAAGTCAAATCGGAA CACAAAAGUCAAAUCGGAA (SEQ ID NO: 165) (SEQ ID NO: 179) ATTTCAATATAAGATTCGG AUUUCAAUAUAAGAUUCGG (SEQ ID NO: 166) (SEQ ID NO: 180) TGAGGGCTCCACCCTCACGA UGAGGGCUCCACCCUCACGA (SEQ ID NO: 167) (SEQ ID NO: 181) AAGGATTGAGGGCTCCACCC AAGGAUUGAGGGCUCCACCC (SEQ ID NO: 168) (SEQ ID NO: 182) GCTCCACCCTCACGAGTGGG GCUCCACCCUCACGAGUGGG (SEQ ID NO: 169) (SEQ ID NO: 183) TGAGGGCTCCACCCTCACGA UGAGGGCUCCACCCUCACGA (SEQ ID NO: 170) (SEQ ID NO: 184)

The engineered superexon donor encodes a shortened polyA signal to ensure proper transcriptional signals during mRNA generation from corrected genomic edits. The 3′ RACE characterization confirmed the addition of a polyA tail in superexon-corrected transcripts (FIG. 4E). Future efforts aimed to engineer superexon donors with 3′ UTRs optimized for mRNA stability may result in enhanced therapeutic potential. HITI-mediated single exon and superexon gene editing approaches can also be applied to other genetic diseases including those with gene targets, like DMD, that may be too large to fully package in AAV delivery vectors or characterized by a wide-spectrum of patient mutations, including hemophilia, cystic fibrosis, and Neurofibromatosis type 1.

Previously, proof-of-principle HITI-mediated gene corrective strategies characterized editing outcomes by Surveyor analysis, in-out PCR amplification, ddPCR, and TOPO sequencing. In this study, Tn5-transposon-based library preparation methods and unbiased deep sequencing characterization were used for greater resolution of diverse HITI-mediated editing outcomes. Using these methods, genomic site-specific integration of intended donor corrections, inverted donor insertions, indels, AAV-ITR integrations, and AAV-Cas9 coding sequences were detected. Analysis of cDNA edits demonstrated on-target intended splicing and aberrant splicing including intended donor inclusion, inverted donor sequences, Cas9 coding sequences, circular RNAs, multi-exon skips, and alternative splice sites in downstream introns. These results are all consistent with previous observations of unintended editing outcomes using AAV-CRISPR.

Gene editing technologies have garnered incredible enthusiasm for the potential to correct genetic mutations to restore healthy, wild-type gene sequences. However, the majority of gene editing strategies being advanced to clinical trials today involve gene disruption, activation of compensatory factors, introduction of therapeutic genes to non-native “safe-harbor” loci, or the creation of truncated, partially functional gene sequences. The compositions and methods detailed herein represent an important step towards realizing the full potential of genome editing to treat the fundamental cause of genetic disease.

The foregoing description of the specific aspects will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific aspects, without undue experimentation, without departing from the general concept of the present disclosure. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

All publications, patents, patent applications, and/or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and/or other document were individually indicated to be incorporated by reference for all purposes.

For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

Clause 1. A CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.

Clause 2. A CRISPR/Cas-based genome editing system comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.

Clause 3. A CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.

Clause 4. A CRISPR/Cas-based genome editing system comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.

Clause 5. The system of clause 3 or 4, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene.

Clause 6. The system of clause 1, 2, or 5, wherein the gRNA hybridizes to a target sequence within the polynucleotide sequence of SEQ ID NO: 128 or SEQ ID NO: 156.

Clause 7. The system of any one of clauses 3-6, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.

Clause 8. The system of clause 1, 2, or 7, wherein donor sequence comprises the polynucleotide sequence of SEQ ID NO: 53.

Clause 9. The system of any one of clauses 1-8, wherein the fragment of the wild-type dystrophin gene is flanked on both sides by a gRNA spacer and/or a PAM sequence.

Clause 10. The system of any one of clauses 1-9, wherein the gRNA targets an intron that is between exon 51 and exon 52 of the mutant dystrophin gene.

Clause 11. The system of any one of clauses 1-10, wherein the donor sequence comprises multiple exons of the wild-type dystrophin gene or a functional equivalent thereof.

Clause 12. The system of any one of clauses 1-11, wherein the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of the wild-type dystrophin gene or a functional equivalent thereof, or wherein the donor sequence comprises exons 52-79 of the wild-type dystrophin gene or a functional equivalent thereof, or wherein the donor sequence comprises exons 45-79 of the wild-type dystrophin gene or a functional equivalent thereof.

Clause 13. The system of any one of clauses 1-12, wherein exon 52 of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene, or wherein exon 52 of the mutant dystrophin gene is deleted and the intron is juxtaposed to where the deleted exon 52 would be in a corresponding wild-type dystrophin gene.

Clause 14. The system of any one of clauses 1-13, wherein the gRNA binds and targets a polynucleotide sequence comprising: (a) a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (b) a fragment of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (c) a complement of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a fragment thereof; (d) a nucleic acid that is substantially identical to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a complement thereof; or (e) a nucleic acid that hybridizes under stringent conditions to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a complement thereof, or a sequence substantially identical thereto.

Clause 15. The system of any one of clauses 1-14, wherein the gRNA binds and targets or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, or a variant thereof.

Clause 16. The system of any one of clauses 9-15, wherein the gRNA spacer comprises a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, or a variant thereof.

Clause 17. The system of any one of clauses 1-16, wherein the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 64-86, 88, 171-184, a complement thereof, or a variant thereof.

Clause 18. The system of any one of clauses 1-17, wherein the gRNA binds or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 35, 40, and 44, or wherein the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 70, 75, and 79.

Clause 19. The system of any one of clauses 1-18, wherein the donor sequence comprises a polynucleotide sequence selected from SEQ ID NOs: 53-56, 154, and 155.

Clause 20. The system of clause 19, wherein the donor sequence comprises a polynucleotide of SEQ ID NO: 55.

Clause 21. The system of clause 19, wherein the donor sequence comprises a polynucleotide of SEQ ID NO: 56.

Clause 22. The system of any one of clauses 1-21, wherein the Cas protein is a Streptococcus pyogenes Cas9 protein or a Staphylococcus aureus Cas9 protein.

Clause 23. The system of any one of clauses 1-22, wherein the Cas protein comprises an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 19.

Clause 24. The system of any one of clauses 1, 3, and 5-23, wherein the vector is a viral vector.

Clause 25. The system of clause 24, wherein the vector is an Adeno-associated virus (AAV) vector.

Clause 26. The system of clause 25, wherein the AAV vector is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV-10, AAV-11, AAV-12, AAV-13, or AAVrh.74 vector.

Clause 27. The system of clause 26, wherein one of the one or more vectors comprises a polynucleotide sequence selected from SEQ ID NOs: 57-60 and 129-130.

Clause 28. The system of any one of clauses 1-27, wherein the molar ratio between gRNA and donor sequence is 1:1, or 1:5, or from 5:1 to 1:10, or from 1:1 to 1:5.

Clause 29. A recombinant polynucleotide encoding a donor sequence, wherein the donor sequence is flanked on both sides by a gRNA spacer and/or a PAM sequence, and wherein the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of a dystrophin gene.

Clause 30. The system of any one of clauses 1-28 or the recombinant polynucleotide of clause 29, wherein the dystrophin gene is a human dystrophin gene.

Clause 31. The system or the recombinant polynucleotide of clause 30, wherein the system results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.

Clause 32. The system or the recombinant polynucleotide of clause 30 or 31, wherein the donor sequence comprises a polynucleotide sequence comprising exons 52-79 of the human dystrophin gene.

Clause 33. The system or the recombinant polynucleotide of clause 32, wherein the donor sequence comprises the polynucleotide sequence of SEQ ID NO: 55 or SEQ ID NO: 56.

Clause 34. The recombinant polynucleotide of clause 29, wherein the recombinant polynucleotide comprises a sequence selected from SEQ ID NOs: 57-60.

Clause 35. A vector comprising the recombinant polynucleotide of any one of clauses 27-32.

Clause 36. A cell comprising the recombinant polynucleotide of any one of clauses 29-34 or the vector of clause 35.

Clause 37. A composition for restoring dystrophin function in a cell having a mutant dystrophin gene, the composition comprising the system of any one of clauses 1-28 or 30-33, the recombinant polynucleotide of any one of clauses 29-34, or the vector of clause 35.

Clause 38. A kit comprising the system of any one of clauses 1-28 or 30-33, the recombinant polynucleotide of any one of clauses 29-34, or the vector of clause 35, or the composition of clause 35.

Clause 39. A method for restoring dystrophin function in a cell or a subject having a mutant dystrophin gene, the method comprising contacting the cell or the subject with the system of any one of clauses 1-28 or 30-33, the recombinant polynucleotide of any one of clauses 29-34, or the vector of clause 35, or the composition of clause 37.

Clause 40. The method of clause 39, wherein the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.

Clause 41. A method for restoring dystrophin function in a cell or a subject having a disrupted dystrophin gene caused by one or more deleted or mutated exons, the method comprising contacting the cell or the subject with the system of any one of clauses 1-28 or 30-33, the recombinant polynucleotide of any one of clauses 29-34, or the vector of clause 35, or the composition of clause 37.

Clause 42. The method of clause 41, wherein the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.

Clause 43. The method of clause 41 or 42, wherein dystrophin function is restored by inserting one or more wild-type exons of dystrophin gene corresponding to the one or more deleted or mutated exons.

Clause 44. The method of any one of clauses 39-43, wherein the subject is suffering from Duchenne Muscular Dystrophy.

Clause 45. A genome editing system for correcting a dystrophin gene, the system comprising a donor sequence comprising exons 52-79 or exons 45-79 of the wild-type dystrophin gene.

Clause 46. The genome editing system of clause 45, further comprising a nuclease selected from homing endonuclease, zinc finger nuclease, TALEN, and Cas protein.

SEQUENCES SEQ ID NO: 1 NRG (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 2 NGG (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 3 NAG (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 4 NGGNG (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 5 NNAGAAW (W = A or T; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 6 NAAR (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 7 NNGRR (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 8 NNGRRN (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 9 NNGRRT (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 10 NNGRRV (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 11 NNNNGATT (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 12 NNNNGNNN (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 13 NGA (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 14 NNNRRT (R = A or G; N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 15 ATTCCT SEQ ID NO: 16 NGAN (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 17 NGNG (N can be any nucleotide residue, e.g., any of A, G, C, or T) SEQ ID NO: 18 Streptccoccus pyogenes Cas9 MDKKYSTGLDTGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLTGALLFDSGETAEATRLKRTA RRRYTRRKNRTCYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTTY HLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINAS GVDAKAILSARLSKSRRLENLTAQLPGEKKNGLFGNLTALSLGLTPNFKSNFDLAEDAKLQLSKDTYD DDLDNLLAQTGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVR QQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNG SIPHQIHLGELHAILRRQEDEYPFLKDNREKIEKILTFRIPYYVGPLARGNSREAWMTRKSEETTTPW NFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQ KKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRENASLGTYHDLLKIIKDKDFLDNEEN EDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTTL DELKSDGFANRNEMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHTANLAGSPAIKKGILQTVKVVDELV KVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYL QNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWR QLLNAKLITQRKEDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIRE VKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK MTAKSEQETGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLS MPQVNIVKKTEVQTGGFSKESILPKRNSDKLTARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKK LKSVKELLGITTMERSSFEKNPIDELEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGN AYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTTDRKRYTSTKEVLDATLIHQSITGLYETRI DLSQLGGD SEQ ID NO: 19 Staphylococcus aureus Cas9 molecule MKRNYILGLDTGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLKRRRRHRIQRVK KLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHNVNEVEEDTGNELSTKE QISRNSKALEEKYVAELQLERLKKDGEVRGSINREKTSDYVKEAKQLLKVQKAYHQLDQSFIDTYIDL LETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFPEELRSVKYAYNADLYNALNDLNNLVITRDEN EKLEYYEKEQIIENVEKQKKKPTLKQTAKEILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKE IIENAELLDQTAKILTTYQSSEDIQEELTNLNSELTQEEIEQISNLKGYTGTHNLSLKAINLILDELW HTNDNQTAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQSIKVINAIIKKYGLPNDIII ELAREKNSKDAQKMINEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHDMQEGKCLYSLEAIPLE DLLNNPFNYEVDHIIPRSVSFDNSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISYETFKKHILNLA KGKGRISKTKKEYLLEERDINRFSVQKDFINRNLVDTRYATRGLMNLLRSYFRVNNLDVKVKSINGGF TSFLRRKWKFKKERNKGYKHHAEDALITANADFIFKEWKKLDKAKKVMENQMFEEKQAESMPEIETEQ EYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNRELINDTLYSTRKDDKGNTLIVNNLNGLYDKDNDKL KKLINKSPEKLLMYHHDPQTYQKLKLIMEQYGDEKNPLYKYYEETGNYLTKYSKKDNGPVIKKIKYYG NKLNAHLDITDDYPNSRNKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKK LKKISNQAEFTASFYNNDLIKINGELYRVTGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTT ASKTQSIKKYSTDILGNLYEVKSKKHPQIIKKG SEQ ID NO: 20 codon optimized polynucleotide encoding S. pyogenes Cas9 atggataaaa agtacagcat cgggctggac atcggtacaa actcagtggg gtgggccgtg attacggacg agtacaaggt accctccaaa aaatttaaag tgctgggtaa cacggacaga cactctataa agaaaaatct tattggagcc ttgctgttcg actcaggcga gacagccgaa gccacaaggt tgaagcggac cgccaggagg cggtatacca ggagaaagaa ccgcatatgc tacctgcaag aaatcttcag taacgagatg gcaaaggttg acgatagctt tttccatcgc  ctggaagaat cctttcttgt tgaggaagac aagaagcacg aacggcaccc catctttggc aatattgtcg acgaagtggc atatcacgaa aagtacccga ctatctacca cctcaggaag aagctggtgg actctaccga taaggcggac ctcagactta tttatttggc actcgcccac atgattaaat ttagaggaca tttcttgatc gagggcgacc tgaacccgga caacagtgac gtcgataagc tgttcatcca acttgtgcag acctacaatc aactgttcga agaaaaccct ataaatgctt caggagtcga cgctaaagca atcctgtccg cgcgcctctc aaaatctaga agacttgaga atctgattgc tcagttgccc ggggaaaaga aaaatggatt gtttggcaac  ctgatcgccc tcagtctcgg actgacccca aatttcaaaa gtaacttcga cctggccgaa gacgctaagc tccagctgtc caaggacaca tacgatgacg acctcgacaa tctgctggcc cagattgggg atcagtacgc cgatctcttt ttggcagcaa agaacctgtc cgacgccatc ctgttgagcg atatcttgag agtgaacacc gaaattacta aagcacccct tagcgcatct atgatcaagc ggtacgacga gcatcatcag gatctgaccc tgctgaaggc tcttgtgagg caacagctcc ccgaaaaata caaggaaatc ttctttgacc agagcaaaaa cggctacgct ggctatatag atggtggggc cagtcaggag gaattctata aattcatcaa gcccattctc gagaaaatgg acggcacaga ggagttgctg gtcaaactta acagggagga cctgctgcgg aagcagcgga cctttgacaa cgggtctatc ccccaccaga ttcatctggg cgaactgcac gcaatcctga ggaggcagga ggatttttat ccttttctta aagataaccg cgagaaaata gaaaagattc ttacattcag gatcccgtac tacgtgggac ctctcgcccg gggcaattca cggtttgcct ggatgacaag gaagtcagag gagactatta caccttggaa cttcgaagaa gtggtggaca agggtgcatc tgcccagtct ttcatcgagc ggatgacaaa ttttgacaag aacctcccta atgagaaggt gctgcccaaa cattctctgc tctacgagta ctttaccgtc tacaatgaac tgactaaagt caagtacgtc accgagggaa tgaggaagcc ggcattcctt agtggagaac agaagaaggc gattgtagac ctgttgttca agaccaacag gaaggtgact gtgaagcaac ttaaagaaga ctactttaag aagatcgaat gttttgacag tgtggaaatt tcaggggttg aagaccgctt caatgcgtca ttggggactt accatgatct tctcaagatc ataaaggaca aagacttcct ggacaacgaa gaaaatgagg atattctcga agacatcgtc ctcaccctga ccctgttcga agacagggaa atgatagaag agcgcttgaa aacctatgcc  cacctcttcg acgataaagt tatgaagcag ctgaagcgca ggagatacac aggatgggga agattgtcaa ggaagctgat caatggaatt agggataaac agagtggcaa gaccatactg gatttcctca aatctgatgg cttcgccaat aggaacttca tgcaactgat tcacgatgac tctcttacct tcaaggagga cattcaaaag gctcaggtga gcgggcaggg agactccctt catgaacaca tcgcgaattt ggcaggttcc cccgctatta aaaagggcat ccttcaaact gtcaaggtgg tggatgaatt ggtcaaggta atgggcagac ataagccaga aaatattgtg atcgagatgg cccgcgaaaa ccagaccaca cagaagggcc agaaaaatag tagagagcgg atgaagagga tcgaggaggg catcaaagag ctgggatctc agattctcaa agaacacccc gtagaaaaca cacagctgca gaacgaaaaa ttgtacttgt actatctgca gaacggcaga gacatgtacg tcgaccaaga acttgatatt aatagactgt ccgactatga cgtagaccat atcgtgcccc agtccttcct gaaggacgac tccattgata acaaagtctt gacaagaagc gacaagaaca ggggtaaaag tgataatgtg cctagcgagg aggtggtgaa aaaaatgaag aactactggc gacagctgct taatgcaaag ctcattacac aacggaagtt cgataatctg acgaaagcag agagaggtgg cttgtctgag ttggacaagg cagggtttat taagcggcag ctggtggaaa ctaggcagat cacaaagcac gtggcgcaga ttttggacag ccggatgaac acaaaatacg acgaaaatga taaactgata cgagaggtca aagttatcac gctgaaaagc aagctggtgt ccgattttcg gaaagacttc cagttctaca aagttcgcga gattaataac taccatcatg ctcacgatgc gtacctgaac gctgttgtcg ggaccgcctt gataaagaag tacccaaagc tggaatccga gttcgtatac ggggattaca aagtgtacga tgtgaggaaa atgatagcca agtccgagca ggagattgga aaggccacag ctaagtactt cttttattct aacatcatga atttttttaa gacggaaatt accctggcca acggagagat cagaaagcgg ccccttatag agacaaatgg tgaaacaggt gaaatcgtct gggataaggg cagggatttc gctactgtga ggaaggtgct gagtatgcca caggtaaata tcgtgaaaaa aaccgaagta cagaccggag gattttccaa ggaaagcatt ttgcctaaaa gaaactcaga caagctcatc gcccgcaaga aagattggga ccctaagaaa tacgggggat ttgactcacc caccgtagcc tattctgtgc tggtggtagc taaggtggaa aaaggaaagt ctaagaagct gaagtccgtg aaggaactct tgggaatcac tatcatggaa agatcatcct ttgaaaagaa ccctatcgat ttcctggagg ctaagggtta caaggaggtc aagaaagacc tcatcattaa actgccaaaa tactctctct tcgagctgga aaatggcagg aagagaatgt tggccagcgc cggagagctg caaaagggaa acgagcttgc tctgccctcc aaatatgtta attttctcta tctcgcttcc cactatgaaa agctgaaagg gtctcccgaa gataacgagc agaagcagct gttcgtcgaa cagcacaagc actatctgga tgaaataatc gaacaaataa gcgagttcag caaaagggtt atcctggcgg atgctaattt ggacaaagta ctgtctgctt ataacaagca ccgggataag cctattaggg aacaagccga gaatataatt cacctcttta cactcacgaa tctcggagcc cccgccgcct tcaaatactt tgatacgact atcgaccgga aacggtatac cagtaccaaa gaggtcctcg atgccaccct catccaccag tcaattactg gcctgtacga aacacggatc gacctctctc aactgggcgg cgactag SEQ ID NO: 21 codon optimized nucleic acid sequences encoding S. aureus Cas9 atgaaaagga actacattct ggggctggac atcgggatta caagcgtggg gtatgggatt attgactatg aaacaaggga cgtgatcgac gcaggcgtca gactgttcaa ggaggccaac gtggaaaaca atgagggacg gagaagcaag aggggagcca ggcgcctgaa acgacggaga aggcacagaa tccagagggt gaagaaactg ctgttcgatt acaacctgct gaccgaccat tctgagctga gtggaattaa tccttatgaa gccagggtga aaggcctgag tcagaagctg tcagaggaag agttttccgc agctctgctg cacctggcta agcgccgagg agtgcataac gtcaatgagg tggaagagga caccggcaac gagctgtcta caaaggaaca gatctcacgc aatagcaaag ctctggaaga gaagtatgtc gcagagctgc agctggaacg gctgaagaaa gatggcgagg tgagagggtc aattaatagg ttcaagacaa gcgactacgt caaagaagcc aagcagctgc tgaaagtgca gaaggcttac caccagctgg atcagagctt catcgatact tatatcgacc tgctggagac tcggagaacc tactatgagg gaccaggaga agggagcccc ttcggatgga aagacatcaa ggaatggtac gagatgctga tgggacattg cacctatttt ccagaagagc tgagaagcgt caagtacgct tataacgcag atctgtacaa cgccctgaat gacctgaaca acctggtcat caccagggat gaaaacgaga aactggaata ctatgagaag ttccagatca tcgaaaacgt gtttaagcag aagaaaaagc ctacactgaa acagattgct aaggagatcc tggtcaacga agaggacatc aagggctacc gggtgacaag cactggaaaa ccagagttca ccaatctgaa agtgtatcac gatattaagg acatcacagc acggaaagaa atcattgaga acgccgaact gctggatcag attgctaaga tcctgactat ctaccagagc tccgaggaca tccaggaaga gctgactaac ctgaacagcg agctgaccca ggaagagatc gaacagatta gtaatctgaa ggggtacacc ggaacacaca acctgtccct gaaagctatc aatctgattc tcgatgagct gtggcataca aacgacaatc agattgcaat ctttaaccgg ctgaagctgg tcccaaaaaa ggtggacctg agtcagcaga aagagatccc aaccacactg gtggacgatt tcattctgtc acccgtggtc aagcggagct tcatccagag catcaaagtg atcaacgcca tcatcaagaa gtacggcctg cccaatgata tcattatcga gctggctagg gagaagaaca gcaaggacgc acagaagatg atcaatgaga tgcagaaacg aaaccggcag accaatgaac gcattgaaga gattatccga actaccggga aagagaacgc aaagtacctg attgaaaaaa tcaagctgca cgatatgcag gagggaaagt gtctgtattc tctggaggcc tccccctgg aggacctgct gaacaatcca ttcaactacg aggtcgatca tattatcccc agaagcgtgt ccttcgacaa ttcctttaac aacaaggtgc tggtcaagca ggaagagaac tctaaaaagg gcaataggac tcctttccag tacctgtcta gttcagattc caagatctct tacgaaacct ttaaaaagca cattctgaat ctggccaaag gaaagggccg catcagcaag accaaaaagg agtacctgct ggaagagcgg gacatcaaca gattctccgt ccagaaggat tttattaacc ggatcctatt ggacacaaga tacgctactc gcggcctgat gaatctgctg cgatcctatt tccgggtgaa caatctggat gtgaaagtca agtccatcaa cggcgggttc acatcttttc tgaggcgcaa atggaagttt aaaaaggagc gcaacaaagg gtacaagcac catgccgaag atgctctgat tatcgcaaat gccgacttca tctttaagga gtggaaaaag ctggacaaag ccaagaaagt gatggagaac cagatgttcg aagagaagca ggccgaatct atgcccgaaa tcgagacaga acaggagtac aaggagattt tcatcactcc tcaccagatc aagcatatca aggatttcaa ggactacaag tactctcacc gggtggataa aaagcccaac agagagctga tcaatgacac cctgtatagt acaagaaaag acgataaggg gaataccctg attgtgaaca atctgaacgg actgtacgac aaagataatg acaagctgaa aaagctgatc aacaaaagtc ccgagaagct gctgatgtac caccatgatc ctcagacata tcagaaactg aagctgatta tggagcagta cggcgacgag aagaacccac tgtataagta ctatgaagag actgggaact acctgaccaa gtatagcaaa aaggataatg gccccgtgat caagaagatc aagtactatg ggaacaagct gaatgcccat ctggacatca cagacgatta coctaacagt cgcaacaagg tggtcaagct gtcactgaag ccatacagat tcgatgtcta tctggacaac ggcgtgtata aatttgtgac tgtcaagaat ctggatgtca tcaaaaagga gaactactat gaagtgaata gcaagtgcta cgaagaggct aaaaagctga aaaagattag caaccaggca gagttcatcg cctcctttta caacaacgac ctgattaaga tcaatggcga actgtatagg gtcatcgggg tgaacaatga tctgctgaac cccattgaag tgaatatgat tgacatcact taccgagagt atctggaaaa catgaatgat aagcgccccc ctcgaattat caaaacaatt gcctctaaga ctcagagtat caaaaagtac tcaaccgaca ttctgggaaa cctgtatgag gtgaagagca aaaagcaccc tcagattatc aaaaagggc SEQ ID NO: 22 codon optimized nucleic acid sequences encoding S. aureus Cas9 atgaagcgga actacatcct gggcctggac atcggcatca ccagcgtggg ctacggcatc atcgactacg agacacggga cgtgatcgat gccggcgtgc ggctgttcaa agaggccaac  gtggaaaaca acgagggcag gcggagcaag agaggcgcca gaaggctgaa gcggcggagg cggcatagaa tccagagagt gaagaagctg ctgttcgact acaacctgct gaccgaccac agcgagctga gcggcatcaa cccctacgag gccagagtga agggcctgag ccagaagctg agcgaggaag agttctctgc cgccctgctg cacctggcca agagaagagg cgtgcacaac gtgaacgagg tggaagagga caccggcaac gagctgtcca ccaaagagca gatcagccgg aacagcaagg ccctggaaga gaaatacgtg gccgaactgc agctggaacg gctgaagaaa gacggcgaag tgcggggcag catcaacaga ttcaagacca gcgactacgt gaaagaagcc aaacagctgc tgaaggtgca gaaggcctac caccagctgg accagagctt catcgacacc tacatcgacc tgctggaaac ccggcggacc tactatgagg gacctggcga gggcagcccc ttcggctgga aggacatcaa agaatggtac gagatgctga tgggccactg cacctacttc cccgaggaac tgcggagcgt gaagtacgcc tacaacgccg acctgtacaa cgccctgaac gacctgaaca atctcgtgat caccagggac gagaacgaga agctggaata ttacgagaag ttccagatca tcgagaacgt gttcaagcag aagaagaagc ccaccctgaa gcagatcgcc aaagaaatcc tcgtgaacga agaggatatt aagggctaca gagtgaccag caccggcaag cccgagttca ccaacctgaa ggtgtaccac gacatcaagg acattaccgc ccggaaagag attattgaga acgccgagct getggatcag attgccaaga tcctgaccat ctaccagagc agcgaggaca tccaggaaga actgaccaat ctgaactccg agctgaccca ggaagagatc gagcagatct ctaatctgaa gggctatacc ggcacccaca acctgagcct gaaggccatc aacctgatcc tggacgagct gtggcacacc aacgacaacc agatcgctat cttcaaccgg ctgaagctgg tgcccaagaa ggtggacctg tcccagcaga aagagatccc caccaccctg gtggacgact tcatcctgag ccccgtcgtg aagagaagct tcatccagag catcaaagtg atcaacgcca tcatcaagaa gtacggcctg cccaacgaca tcattatcga gctggcccgc gagaagaact ccaaggacgc ccagaaaatg atcaacgaga tgcagaagcg gaaccggcag accaacgagc ggatcgagga aatcatccgg accaccggca aagagaacgc caagtacctg atcgagaaga tcaagctgca cgacatgcag gaaggcaagt gcctgtacag cctggaagcc atccctctgg aagatctgct gaacaacccc ttcaactatg aggtggacca catcatcccc agaagcgtgt ccttcgacaa cagcttcaac aacaaggtgc tcgtgaagca ggaagaaaac agcaagaagg gcaaccggac cccattccag tacctgagca gcagcgacag caagatcagc tacgaaacct tcaagaagca catcctgaat ctggccaagg gcaagggcag aatcagcaag accaagaaag agtatctgct ggaagaacgg gacatcaaca ggttctccgt gcagaaagac ttcatcaacc ggaacctggt ggataccaga tacgccacca gaggcctgat gaacctgctg cggagctact tcagagtgaa caacctggac gtgaaagtga agtccatcaa tggcggcttc accagctttc tgcggcggaa gtggaagttt aagaaagagc ggaacaaggg gtacaagcac cacgccgagg acgccctgat cattgccaac gccgatttca tcttcaaaga gtggaagaaa ctggacaagg ccaaaaaagt gatggaaaac cagatgttcg aggaaaagca ggccgagagc atgcccgaga tcgaaaccga gcaggagtac aaagagatct tcatcacccc ccaccagatc aagcacatta aggacttcaa ggactacaag tacagccacc gggtggacaa gaagcctaat agagagecga ttaacgacac cctgtactcc acccggaagg acgacaaggg caacaccctg atcgtgaaca atctgaacgg cctgtacgac aaggacaatg acaagctgaa aaagctgatc aacaagagcc ccgaaaagct gctgatgtac caccacgacc cccagaccta ccagaaactg aagctgatta tggaacagta cggcgacgag aagaatcccc tgtacaagta ctacgaggaa accgggaact acctgaccaa gtactccaaa aaggacaacg gccccgtgat caagaagatt aagtattacg gcaacaaact gaacgcccat ctggacatca ccgacgacta ccccaacagc agaaacaagg tcgtgaagct gtccctgaag ccctacagat tcgacgtgta cctggacaat ggcgtgtaca agttcgtgac cgtgaagaat ctggatgtga tcaaaaaaga aaactactac gaagtgaata gcaagtgcta tgaggaagct aagaagctga agaagatcag caaccaggcc gagtttatcg cctccttcta caacaacgat ctgatcaaga tcaacggcga gctgtataga gtgatcggcg tgaacaacga cctgctgaac cggatcgaag tgaacatgat cgacatcacc taccgcgagt acctggaaaa catgaacgac aagaggcccc ccaggatcat taagacaatc gectccaaga cccagagcat taagaagtac agcacagaca ttctgggcaa cctgtatgaa gtgaaatcta agaagcaccc tcagatcatc aaaaagggc SEQ ID NO: 23 codon optimized nucleic acid sequence encoding S. aureus Cas9 atgaagcgca actacatcct cggactggac atcggcatta cctccgtggg atacggcatc atcgattacg aaactaggga tgtgatcgac gctggagtca ggctgttcaa agaggcgaac gtggagaaca acgaggggcg gcgctcaaag aggggggccc gccggctgaa gcgccgccgc agacatagaa tccagcgcgt gaagaagctg ctgttcgact acaaccttct gaccgaccac tccgaacttt ccggcatcaa cccatatgag gctagagtga agggattgtc ccaaaagctg tccgaggaag agttctccgc cgcgttgctc cacctcgcca agcgcagggg agtgcacaat gtgaacgaag tggaagaaga taccggaaac gagctgtcca ccaaggagca gatcagccgg aactccaagg ccctggaaga gaaatacgtg gcggaactgc aactggagcg gctgaagaaa gacggagaag tgcgcggctc gatcaaccgc ttcaagacct cggactacgt gaaggaggcc aagcagctcc tgaaagtgca aaaggcctat caccaacttg accagtcctt tatcgatacc tacatcgatc tgctcgagac tcggcggact tactacgagg gtccagggga gggctcccca tttggttgga aggatattaa ggagtggtac gaaatgctga tgggacactg cacatacttc cctgaggagc tgcggagcgt gaaatacgca tacaacgcag acctgtacaa cgcgctgaac gacctgaaca atctcgtgat cacccgggac gagaacgaaa agctcgagta ttacgaaaag ttccagatta ttgagaacgt gttcaaacag aagaagaagc cgacactgaa gcagattgcc aaggaaatcc tcgtgaacga agaggacatc aagggctatc gagtgacctc aacgggaaag ccggagttca ccaatctgaa ggtctaccac gacatcaaag acattaccgc ccggaaggag atcattgaga acgcggagct gttggaccag attgcgaaga ttctgaccat ctaccaatcc tccgaggata ttcaggaaga actcaccaac ctcaacagcg aactgaccca ggaggagata gagcaaatct ccaacctgaa gggctacacc ggaactcata acctgagcct gaaggccatc aacttgatcc tggacgagct gtggcacacc aacgataacc agatcgctat tttcaatcgg ctgaagctgg tccccaagaa agtggacctc tcacaacaaa aggagatccc tactaccctt gtggacgatt tcattctgtc ccccgtggtc aagagaagct tcatacagtc aatcaaagtg atcaatgcca ttatcaagaa atacggtctg cocaacgaca ttatcattga gctcgcccgc gagaagaact cgaaggacgc ccagaagatg attaacgaaa tgcagaagag gaaccgacag actaacgaac ggatcgaaga aatcatccgg accaccggga aggaaaacgc gaagtacctg atcgaaaaga tcaagctcca tgacatgcag gaaggaaagt gtctgtactc gctggaggcc attccgctgg aggacttgct gaacaaccct tttaactacg aagtggatca tatcattccg aggagcgtgt cattcgacaa ttccttcaac aacaaggtcc tcgtgaagca ggaggaaaac tcgaagaagg gaaaccgcac gccgttccag tacctgagca gcagcgactc caagatttcc tacgaaacct tcaagaagca catcctcaac ctggcaaagg ggaagggtcg catctccaag accaagaagg aatatctgct ggaagaaaga gacatcaaca gattctccgt gcaaaaggac ttcatcaace gcaacctcgt ggatactaga tacgctacte ggggtctgat gaacctcctg agaagctact ttagagtgaa caatctggac gtgaaggtca agtcgattaa cggaggtttc acctccttcc tgcggcgcaa gtggaagttc aagaaggaac ggaacaaggg ctacaagcac cacgccgagg acgccctgat cattgccaac gccgacttca tcttcaaaga atggaagaaa cttgacaagg ctaagaaggt catggaaaac cagatgttcg aagaaaagca ggccgagtct atgcctgaaa tcgagactga acaggagtac aaggaaatct ttattacgcc acaccagatc aaacacatca aggatttcaa ggattacaag tactcacatc gcgtggacaa aaagccgaac agggaactga tcaacgacac cctctactcc acccggaagg atgacaaagg gaataccctc atcgtcaaca accttaacgg cctgtacgac aaggacaacg ataagctgaa gaagctcatt aacaagtcgc ccgaaaagtt gctgatgtac caccacgacc ctcagactta ccagaagctc aagctgatca tggagcagta tggggacgag aaaaacccgt tgtacaagta ctacgaagaa actgggaatt atctgactaa gtactccaag aaagataacg gccccgtgat taagaagatt aagtactacg gcaacaagct gaacgcccat ctggacatca ccgatgacta ccctaattcc cgcaacaagg tcgtcaagct gagcctcaag ccctaccggt ttgatgtgta ccttgacaat ggagtgtaca agttcgtgac tctgaagaac cttgacgtga tcaagaagga gaactactac  gaagtcaact ccaagtgcta cgaggaagca aagaagttga agaagatctc gaaccaggcc gagttcattg cctccttcta taacaacgac ctgattaaga tcaacggcga actgtaccgc gtcattggcg tgaacaacga tctcctgaac cgcatcgaag tgaacatgat cgacatcact taccgggaat acctggagaa tatgaacgac aagcgcccgc cccggatcat taagactatc gcctcaaaga cccagtcgat caagaagtac agcaccgaca tcctgggcaa cctgtacgag gtcaaatcga agaagcaccc ccagatcatc aagaaggga SEQ ID NO: 24 codon optimized nucleic acid sequence encoding S. aureus Cas9 atggccccaaagaagaagcggaaggtcggtatccacggagtcccagcagccaagcggaactacatcct gggcctggacatcggcatcaccagcgtgggctacggcatcatcgactacgagacacgggacgtgatcg atgccggcgtgcggctgttcaaagaggccaacgtggaaaacaacgagggcaggcggagcaagagaggc gccagaaggctgaagcggcggaggcggcatagaatccagagagtgaagaagctgctgttcgactacaa cctgctgaccgaccacagcgagctgagcggcatcaacccctacgaggccagagtgaagggcctgagcc agaagctgagcgaggaagagttctctgccgccctgctgcacctggccaagagaagaggcgtgcacaac gtgaacgaggtggaagaggacaccggcaacgagctgtccaccagagagcagatcagccggaacagcaa ggccctggaagagaaatacgtggccgaactgcagctggaacggctgaagaaagacggcgaagtgcggg gcagcatcaacagattcaagaccagcgactacgtgaaagaagccaaacagctgctgaaggtgcagaag ctatgagggacctggcgagggcagccccttcggctggaaggacatcaaagaatggtacgagatgctga tgggccactgcacctacttccccgaggaactgcggagcgtgaagtacgcctacaacgccgacctgtac aacgccctgaacgacctgaacaatctcgtgatcaccagggacgagaacgagaagctggaatattacga gaagttccagatcatcgagaacgtgttcaagcagaagaagaagcccaccctgaagcagatcgccaaag aaatcctcgtgaacgaagaggatattaagggctacagagtgaccagcaccggcaagcccgagttcacc aacctgaaggtgtaccacgacatcaaggacattaccgcccggaaagagattattgagaacgccgagct gctggatcagattgccaagatcctgaccatctaccagagcagcgaggacatccaggaagaactgacca atctgaactccgagctgacccaggaagagatcgagcagatctctaatctgaagggctataccggcacc cacaacctgagcctgaaggccatcaacctgatcctggacgagctgtggcacaccaacgacaaccagat cgctatcttcaaccggctgaagctggtgcccaagaaggtggacctgtcccagcagaaagagatcccca ccaccctggtggacgacttcatcctgagccccgtcgtgaagagaagcttcatccagagcatcaaagtg atcaacgccatcatcaagaagtacggcctgcccaacgacatcattatcgagctggcccgcgagaagaa ctccaaggacgcccagaaaatgatcaacgagatgcagaagcggaaccggcagaccaacgagcggatcg aggaaatcatccggaccaccggcaaagagaacgccaagtacctgatcgagaagatcaagctgcacgac atgcaggaaggcaagtgcctgtacagcctggaagccatccctctggaagatctgctgaacaacccctt caactatgaggtggaccacatcatccccagaagcgtgtccttcgacaacagcttcaacaacaaggtgc tcgtgaagcaggaagaaaacagcaagaagggcaaccggaccccattccagtacctgagcagcagcgac agcaagatcagctacgaaaccttcaagaagcacatcctgaatctggccaagggcaagggcagaatcag caagaccaagaaagagtatctgctggaagaacgggacatcaacaggttctccgtgcagaaagacttca tcaaccggaacctggtggataccagatacgccaccagaggcctgatgaacctgctgcggagctacttc agagtgaacaacctggacgtgaaagtgaagtccatcaatggcggcttcaccagctttctgcggcggaa gtggaagtttaagaaagagcggaacaaggggtacaagcaccacgccgaggacgccctgatcattgcca acgccgatttcatcttcaaagagtggaagaaactggacaaggccaaaaaagtgatggaaaaccagatg ttcgaggaaaggcaggccgagagcatgcccgagatcgaaaccgagcaggagtacaaagagatcttcat caccccccaccagatcaagcacattaaggacttcaaggactacaagtacagccaccgggtggacaaga agcctaatagagagctgattaacgacaccctgtactccacccggaaggacgacaagggcaacaccctg atcgtgaacaatctgaacggcctgtacgacaaggacaatgacaagctgaaaaagctgatcaacaagag ccccgaaaagctgctgatgtaccaccacgacccccagacctaccagaaactgaagctgattatggaac agtacggcgacgagaagaatcccctgtacaagtactacgaggaaaccgggaactacctgaccaagtac tccaaaaaggacaacggccccgtgatcaagaagattaagtattacggcaacaaactgaacgcccatct ggacatcaccgacgactaccccaacagcagaaacaaggtcgtgaagctgtccctgaagccctacagat tcgacgtgtacctggacaatggcgtgtacaagttcgtgaccgtgaagaatctggatgtgatcaaaaaa gaaaactactacgaagtgaatagcaagtgctatgaggaagctaagaagctgaagaagatcagcaacca ggccgagtttatcgcctccttctacaacaacgatctgatcaagatcaacggcgagctgtatagagtga tcggcgtgaacaacgacctgctgaaccggatcgaagtgaacatgatcgacatcacctaccgcgagtac ctggaaaacatgaacgacaagaggccccccaggatcattaagacaatcgcctccaagacccagagcat taagaagtacagcacagacattctgggcaacctgtatgaagtgaaatctaagaagcaccctcagatca tcaaaaagggcaaaaggccggcggccacgaaaaaggccggccaggcaaaaaagaaaaag SEQ ID NO: 25 codon optimized nucleic acid sequence encoding S. aureus Cas9 accggtgcca ccatgtaccc atacgatgtt ccagattacg cttcgccgaa gaaaaagcgc aaggtcgaag cgtccatgaa aaggaactac attctggggc tggacatcgg gattacaagc  gtggggtatg ggattattga ctatgaaaca agggacgtga tcgacgcagg cgtcagactg ttcaaggagg ccaacgtgga aaacaatgag ggacggagaa gcaagagggg agccaggcgc ctgaaacgac ggagaaggca cagaatccag agggtgaaga aactgctgtt cgattacaac ctgctgaccg accattctga gctgagtgga attaatcctt atgaagccag ggtgaaaggc  ctgagtcaga agctgtcaga ggaagagttt tccgcagctc tgctgcacct ggctaagcgc cgaggagtgc ataacgtcaa tgaggtggaa gaggacaccg gcaacgagct gtctacaaag gaacagatct cacgcaatag caaagctctg gaagagaagt atgtcgcaga gctgcagctg gaacggctga agaaagatgg cgaggtgaga gggtcaatta ataggttcaa gacaagcgac tacgtcaaag aagccaagca gctgctgaaa gtgcagaagg cttaccacca gctggatcag agcttcatcg atacttatat cgacctgctg gagactcgga gaacctacta tgagggacca ggagaaggga gccccttcgg atggaaagac atcaaggaat ggtacgagat gctgatggga cattgcacct attttccaga agagctgaga agcgtcaagt acgcttataa cgcagatct tacaacgccc tgaatgacct gaacaacctg gtcatcacca gggatgaaaa cgagaaactg gaatactatg agaagttcca gatcatcgaa aacgtgttta agcagaagaa aaagcctaca ctgaaacaga ttgctaagga gatcctggtc aacgaagagg acatcaaggg ctaccgggtg acaagcactg gaaaaccaga gttcaccaat ctgaaagtgt atcacgatat taaggacatc acagcacgga aagaaatcat tgagaacgcc gaactgctgg atcagattgc taagatcctg actatctacc agagctccga ggacatccag gaagagctga ctaacctgaa cagcgagctg acccaggaag agatcgaaca gattagtaat ctgaaggggt acaccggaac acacaacctg tccctgaaag ctatcaatct gattctggat gagctgtggc atacaaacga caatcagatt gcaatcttta accggctgaa gctggtccca aaaaaggtgg acctgagtca gcagaaagag atcccaacca cactggtgga cgatttcatt ctgtcacccg tggtcaagcg gagcttcatc cagagcatca aagtgatcaa cgccatcatc aagaagtacg gcctgcccaa tgatatcatt atcgagctgg ctagggagaa gaacagcaag gacgcacaga agatgatcaa tgagatgcag aaacgaaacc ggcagaccaa tgaacgcatt gaagagatta tccgaactac cgggaaagag aacgcaaagt acctgattga aaaaatcaag ctgcacgata tgcaggaggg aaagtgtctg tattctctgg aggccatccc cctggaggac ctgctgaaca atccattcaa ctacgaggtc gatcatatta tccccagaag cgtgtccttc gacaattcct ttaacaacaa ggtgctggtc aagcaggaag agaactctaa aaagggcaat aggactcctt tccagtacct gtctagttca gattccaaga tctcttacga aacctttaaa aagcacattc tgaatctggc caaaggaaag ggccgcatca gcaagaccaa aaaggagtac ctgctggaag agcgggacat caacagattc tccgtccaga aggattttat taaccggaat ctggtggaca caagatacgc tactcgcggc ctgatgaatc tgctgcgatc ctatttccgg gtgaacaatc tggatgtgaa agtcaagtcc atcaacggcg ggttcacatc ttttctgagg cgcaaatgga agtttaaaaa ggagcgcaac aaagggtaca agcaccatgc cgaagatgct ctgattatcg caaatgccga cttcatcttt aaggagtgga aaaagctgga caaagccaag aaagtgatgg agaaccagat gttcgaagag aagcaggccg aatctatgcc cgaaatcgag acagaacagg agtacaagga gattttcatc actcctcacc agatcaagca tatcaaggat ttcaaggact acaagtactc tcaccgggtg gataaaaagc ccaacagaga gctgatcaat gacaccctgt atagtacaag aaaagacgat aaggggaata ccctgattgt gaacaatctg aacggactgt acgacaaaga taatgacaag ctgaaaaagc tgatcaacaa aagtcccgag aagctgctga tgtaccacca tgatcctcag acatatcaga aactgaagct gattatggag cagtacggcg acgagaagaa cccactgtat aagtactatg aagagactgg gaactacctg accaagtata gcaaaaagga taatggcccc gtgatcaaga agatcaagta ctatgggaac aagctgaatg cccatctgga catcacagac gattacccta acagtcgcaa caaggtggtc aagctgtcac tgaagccata cagattcgat gtctatctgg acaacggcgt gtataaattt gtgactgtca agaatctgga tgtcatcaaa aaggagaact actatgaagt gaatagcaag tgctacgaag aggctaaaaa gctgaaaaag attagcaacc aggcagagtt catcgcctcc ttttacaaca acgacctgat taagatcaat ggcgaactgt atagggtcat cggggtgaac aatgatctgc tgaaccgcat tgaagtgaat atgattgaca tcacttaccg agagtatctg gaaaacatga atgataagcg cccccctcga attatcaaaa caattgccto taagactcag agtatcaaaa agtactcaac cgacattctg ggaaacctgt atgaggtgaa gagcaaaaag caccctcaga ttatcaaaaa gggctaagaa ttc SEQ ID NO: 26 codon optimized nucleic acid sequences encoding S. aureus Cas9 atggccccaaagaagaagcggaaggtcggtatccacggagtcccagcagccaagcggaactacatcct gggcctggacatcggcatcaccagcgtgggctacggcatcatcgactacgagacacgggacgtgatcg atgccggcgtgcggctgttcaaagaggccaacgtggaaaacaacgagggcaggcggagcaagagaggc gccagaaggctgaagcggcggaggcggcatagaatccagagagtgaagaagctgctgttcgactacaa cctgctgaccgaccacagcgagctgagcggcatcaacccctacgaggccagagtgaagggcctgagcc agaagctgagcgaggaagagttctctgccgccctgctgcacctggccaagagaagaggcgtgcacaac gtgaacgaggtggaagaggacaccggcaacgagctgtccaccaaagagcagatcagccggaacagcaa ggccctggaagagaaatacgtggccgaactgcagctggaacggctgaagaaagacggcgaagtgcggg gcagcatcaacagattcaagaccagcgactacgtgaaagaagccaaacagctgctgaaggtgcagaag gcctaccaccagctggaccagagcttcatcgacacctacatcgacctgctggaaacccggcggaccta ctatgagggacctggcgagggcagccccttcggctggaaggacatcaaagaatggtacgagatgctga tgggccactgcacctacttccccgaggaactgcggagcgtgaagtacgcctacaacgccgacctgtac aacgccctgaacgacctgaacaatctcgtgatcaccagggacgagaacgagaagctggaatattacga gaagttccagatcatcgagaacgtgttcaagcagaagaagaagcccaccctgaagcagatcgccaaag aaatcctcgtgaacgaagaggatattaagggctacagagtgaccagcaccggcaagcccgagttcacc aacctgaaggtgtaccacgacatcaaggacattaccgcccggaaagagattattgagaacgccgagct gctggatcagattgccaagatcctgaccatctaccagagcagcgaggacatccaggaagaactgacca atctgaactccgagctgacccaggaagagatcgagcagatctctaatctgaagggctataccggcacc cacaacctgagcctgaaggccatcaacctgatcctggacgagctgtggcacaccaacgacaaccagat cgctatcttcaaccggctgaagctggtgcccaagaaggtggacctgtcccagcagaaagagatcccca ccaccctggtggacgacttcatcctgagccccgtcgtgaagagaagcttcatccagagcatcaaagtg atcaacgccatcatcaagaagtacggcctgcccaacgacatcattatcgagctggcccgcgagaagaa ctccaaggacgcccagaaaatgatcaacgagatgcagaagcggaaccggcagaccaacgagcggatcg aggaaatcatccggaccaccggcaaagagaacgccaagtacctgatcgagaagatcaagctgcacgac atgcaggaaggcaagtgcctgtacagcctggaagccatccctctggaagatctgctgaacaacccctt caactatgaggtggaccacatcatccccagaagcgtgtccttcgacaacagcttcaacaacaaggtgc tcgtgaagcaggaagaaaacagcaagaagggcaaccggaccccattccagtacctgagcagcagcgac agcaagatcagctacgaaaccttcaagaagcacatcctgaatctggccaagggcaagggcagaatcag caagaccaagaaagagtatctgctggaagaacgggacatcaacaggttctccgtgcagaaagacttca tcaaccggaacctggtggataccagatacgccaccagaggcctgatgaacctgctgcggagctacttc agagtgaacaacctggacgtgaaagtgaagtccatcaatggcggcttcaccagctttctgcggcggaa gtggaagtttaagaaagagcggaacaaggggtacaagcaccacgccgaggacgccctgatcattgcca acgccgatttcatcttcaaagagtggaagaaactggacaaggccaaaaaagtgatggaaaaccagatg ttcgaggaaaagcaggccgagagcatgcccgagatcgaaaccgagcaggagtacaaagagatcttcat caccccccaccagatcaagcacattaaggacttcaaggactacaagtacagccaccgggtggacaaga agcctaatagagagctgattaacgacaccctgtactccacccggaaggacgacaagggcaacaccctg atcgtgaacaatctgaacggcctgtacgacaaggacaatgacaagctgaaaaagctgatcaacaagag ccccgaaaagctgctgatgtaccaccacgacccccagacctaccagaaactgaagctgattatggaac agtacggcgacgagaagaatcccctgtacaagtactacgaggaaaccgggaactacctgaccaagtac tccaaaaaggacaacggccccgtgatcaagaagattaagtattacggcaacaaactgaacgcccatct ggacatcaccgacgactaccccaacagcagaaacaaggtcgtgaagctgtccctgaagccctacagat tcgacgtgtacctggacaatggcgtgtacaagttcgtgaccgtgaagaatctggatgtgatcaaaaaa gaaaactactacgaagtgaatagcaagtgctatgaggaagctaagaagctgaagaagatcagcaacca ggccgagtttatcgcctccttctacaacaacgatctgatcaagatcaacggcgagctgtatagagtga tcggcgtgaacaacgacctgctgaaccggatcgaagtgaacatgatcgacatcacctaccgcgagtac ctggaaaacatgaacgacaagaggccccccaggatcattaagacaatcgcctccaagacccagagcat taagaagtacagcacagacattctgggcaacctgtatgaagtgaaatctaagaagcaccctcagatca tcaaaaagggcaaaaggccggcggccacgaaaaaggccggccaggcaaaaaagaaaaag SEQ ID NO: 27 codon optimized nucleic acid sequences encoding S. aureus Cas9 aagcggaactacatcctgggcctggacatcggcatcaccagcgtgggctacggcatcatcgactacga gacacgggacgtgatcgatgccggcgtgcggctgttcaaagaggccaacgtggaaaacaacgagggca ggcggagcaagagaggcgccagaaggetgaagcggcggaggcggcatagaatccagagagtgaagaag ctgctgttcgactacaacctgctgaccgaccacagcgagctgagcggcatcaacccctacgaggccag agtgaagggcctgagccagaagctgagcgaggaagagttctctgccgccctgctgcacctggccaaga gaagaggcgtgcacaacgtgaacgaggtggaagaggacaccggcaacgagctgtccaccaaagagcag atcagccggaacagcaaggccctggaagagaaatacgtggccgaactgcagctggaacggctgaagaa agacggcgaagtgcggggcagcatcaacagattcaagaccagcgactacgtgaaagaagccaaacagc tgctgaaggtgcagaaggcctaccaccagctggaccagagcttcatcgacacctacatcgacctgctg gaaacccggcggacctactatgagggacctggcgagggcagccccttcggctggaaggacatcaaaga atggtacgagatgctgatgggccactgcacctacttccccgaggaactgcggagcgtgaagtacgcct acaacgccgacctgtacaacgccctgaacgacctgaacaatctcgtgatcaccagggacgagaacgag aagctggaatattacgagaagttccagatcatcgagaacgtgttcaagcagaagaagaagcccaccct gaagcagatcgccaaagaaatcctcgtgaacgaagaggatattaagggctacagagtgaccagcaccg gcaagcccgagttcaccaacctgaaggtgtaccacgacatcaaggacattaccgcccggaaagagatt attgagaacgccgagctgctggatcagattgccaagatcctgaccatctaccagagcagcgaggacat ccaggaagaactgaccaatctgaactccgagctgacccaggaagagatcgagcagatctctaatctga agggctataccggcacccacaacctgagcctgaaggccatcaacctgatcctggacgagctgtggcac accaacgacaaccagatcgctatcttcaaccggctgaagctggtgcccaagaaggtggacctgtccca gcagaaagagatccccaccaccctggtggacgacttcatcctgagccccgtcgtgaagagaagcttca tccagagcatcaaagtgatcaacgccatcatcaagaagtacggcctgcccaacgacatcattatcgag ctggcccgcgagaagaactccaaggacgcccagaaaatgatcaacgagatgcagaagcggaaccggca gaccaacgagcggatcgaggaaatcatccggaccaccggcaaagagaacgccaagtacctgatcgaga agatcaagctgcacgacatgcaggaaggcaagtgcctgtacagcctggaagccatccctctggaagat ctgctgaacaaccccttcaactatgaggtggaccacatcatccccagaagcgtgtccttcgacaacag cttcaacaacaaggtgctcgtgaagcaggaagaaaacagcaagaagggcaaccggaccccattccagt acctgagcagcagcgacagcaagatcagctacgaaaccttcaagaagcacatcctgaatctggccaag ggcaagggcagaatcagcaagaccaagaaagagtatctgctggaagaacgggacatcaacaggttctc cgtgcagaaagacttcatcaaccggaacctggtggataccagatacgccaccagaggcctgatgaacc tgctgcggagctacttcagagtgaacaacctggacgtgaaagtgaagtccatcaatggcggcttcacc agctttctgcggcggaagtggaagtttaagaaagagcggaacaaggggtacaagcaccacgccgagga cgccctgatcattgccaacgccgatttcatcttcaaagagtggaagaaactggacaaggccaaaaaag tgatggaaaaccagatgttcgaggaaaagcaggccgagagcatgcccgagatcgaaaccgagcaggag tacaaagagatcttcatcaccccccaccagatcaagcacattaaggacttcaaggactacaagtacag ccaccgggtggacaagaagcctaatagagagctgattaacgacaccctgtactccacccggaaggacg acaagggcaacaccetgatcgtgaacaatctgaacggcctgtacgacaaggacaatgacaagctgaaa aagctgatcaacaagagccccgaaaagctgctgatgtaccaccacgacccccagacctaccagaaact gaagctgattatggaacagtacggcgacgagaagaatcccctgtacaagtactacgaggaaaccggga actacctgaccaagtactccaaaaaggacaacggccccgtgatcaagaagattaagtattacggcaac aaactgaacgcccatctggacatcaccgacgactaccccaacagcagaaacaaggtcgtgaagctgtc cctgaagccctacagattcgacgtgtacctggacaatggcgtgtacaagttcgtgaccgtgaagaatc tggatgtgatcaaaaaagaaaactactacgaagtgaatagcaagtgctatgaggaagctaagaagctg aagaagatcagcaaccaggccgagtttatcgcctccttctacaacaacgatctgatcaagatcaacgg cgagctgtatagagtgatcggcgtgaacaacgacctgctgaaccggatcgaagtgaacatgatcgaca tcacctaccgcgagtacctggaaaacatgaacgacaagaggccccccaggatcattaagacaatcgcc tccaagacccagagcattaagaagtacagcacagacattctgggcaacctgtatgaagtgaaatctaa gaagcaccctcagatcatcaaaaagggc SEQ ID NO: 28 Vector (pDO242) encoding codon optimized nucleic acid sequence encoding S. aureus Cas9 ctaaattgtaagcgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctcatttttta accaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgtt gttccagtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgt ctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttggggtcgaggtgccgta aagcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtg gcgagaaaggaagggaagaaagcgaaaggagcgggcgctagggcgctggcaagtgtagcggtcacgct gcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcgtcccattcgccattcaggc tgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaaggggga tgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggc cagtgagcgcgcgtaatacgactcactatagggcgaattgggtacCtttaattctagtactatgcaTg cgttgacattgattattgactagttattaatagtaatcaattacggggtcattagttcatagcccata tatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcc cattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgg gtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccc tattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttc ctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatc aatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggag tttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaa tgggcggtaggcgtgtacggtgggaggtctatataagcagagctctctggctaactaccggtgccacc ATGAAAAGGAACTACATTCTGGGGCTGGACATCGGGATTACAAGCGTGGGGTATGGGATTATTGACTA TGAAACAAGGGACGTGATCGACGCAGGCGTCAGACTGTTCAAGGAGGCCAACGTGGAAAACAATGAGG GACGGAGAAGCAAGAGGGGAGCCAGGCGCCTGAAACGACGGAGAAGGCACAGAATCCAGAGGGTGAAG AAACTGCTGTTCGATTACAACCTGCTGACCGACCATTCTGAGCTGAGTGGAATTAATCCTTATGAAGC CAGGGTGAAAGGCCTGAGTCAGAAGCTGTCAGAGGAAGAGTTTTCCGCAGCTCTGCTGCACCTGGCTA AGCGCCGAGGAGTGCATAACGTCAATGAGGTGGAAGAGGACACCGGCAACGAGCTGTCTACAAAGGAA CAGATCTCACGCAATAGCAAAGCTCTGGAAGAGAAGTATGTCGCAGAGCTGCAGCTGGAACGGCTGAA GAAAGATGGCGAGGTGAGAGGGTCAATTAATAGGTTCAAGACAAGCGACTACGTCAAAGAAGCCAAGC AGCTGCTGAAAGTGCAGAAGGCTTACCACCAGCTGGATCAGAGCTTCATCGATACTTATATCGACCTG CTGGAGACTCGGAGAACCTACTATGAGGGACCAGGAGAAGGGAGCCCCTTCGGATGGAAAGACATCAA GGAATGGTACGAGATGOTGATGGGACATTGCACCTATTTTCCAGAAGAGCTGAGAAGCGTCAAGTACG CTTATAACGCAGATCTGTACAACGCCCTGAATGACCTGAACAACCTGGTCATCACCAGGGATGAAAAC GAGAAACTGGAATACTATGAGAAGTTCCAGATCATCGAAAACGTGTTTAAGCAGAAGAAAAAGCCTAC ACTGAAACAGATTGCTAAGGAGATCCTGGTCAACGAAGAGGACATCAAGGGCTACCGGGTGACAAGCA CTGGAAAACCAGAGTTCACCAATCTGAAAGTGTATCACGATATTAAGGACATCACAGCACGGAAAGAA ATCATTGAGAACGCCGAACTGCTGGATCAGATTGCTAAGATCCTGACTATCTACCAGAGCTCCGAGGA CATCCAGGAAGAGCTGACTAACCTGAACAGCGAGCTGACCCAGGAAGAGATCGAACAGATTAGTAATC TGAAGGGGTACACCGGAACACACAACCTGTCCCTGAAAGCTATCAATCTGATTCTGGATGAGCTGTGG CATACAAACGACAATCAGATTGCAATCTTTAACCGGCTGAAGCTGGTCCCAAAAAAGGTGGACCTGAG TCAGCAGAAAGAGATCCCAACCACACTGGTGGACGATTTCATTCTGTCACCCGTGGTCAAGCGGAGCT TCATCCAGAGCATCAAAGTGATCAACGCCATCATCAAGAAGTACGGCCTGCCCAATGATATCATTATC GAGCTGGCTAGGGAGAAGAACAGCAAGGACGCACAGAAGATGATCAATGAGATGCAGAAACGAAACCG GCAGACCAATGAACGCATTGAAGAGATTATCCGAACTACCGGGAAAGAGAACGCAAAGTACCTGATTG AAAAAATCAAGCTGCACGATATGCAGGAGGGAAAGTGTCTGTATTCTCTGGAGGCCATCCCCCTGGAG GACCTGCTGAACAATCCATTCAACTACGAGGTCGATCATATTATCCCCAGAAGCGTGTCCTTCGACAA TTCCTTTAACAACAAGGTGCTGGTCAAGCAGGAAGAGAACTCTAAAAAGGGCAATAGGACTCCTTTCC AGTACCTGTCTAGTTCAGATTCCAAGATCTCTTACGAAACCTTTAAAAAGCACATTCTGAATCTGGCC AAAGGAAAGGGCCGCATCAGCAAGACCAAAAAGGAGTACCTGCTGGAAGAGCGGGACATCAACAGATT CTCCGTCCAGAAGGATTTTATTAACCGGAATCTGGTGGACACAAGATACGCTACTCGCGGCCTGATGA ATCTGCTGCGATCCTATTTCCGGGTGAACAATCTGGATGTGAAAGTCAAGTCCATCAACGGCGGGTTC ACATCTTTTCTGAGGCGCAAATGGAAGTTTAAAAAGGAGCGCAACAAAGGGTACAAGCACCATGCCGA AGATGCTCTGATTATCGCAAATGCCGACTTCATCTTTAAGGAGTGGAAAAAGCTGGACAAAGCCAAGA AAGTGATGGAGAACCAGATGTTCGAAGAGAAGCAGGCCGAATCTATGCCCGAAATCGAGACAGAACAG GAGTACAAGGAGATTTTCATCACTCCTCACCAGATCAAGCATATCAAGGATTTCAAGGACTACAAGTA CTCTCACCGGGTGGATAAAAAGCCCAACAGAGAGCTGATCAATGACACCCTGTATAGTACAAGAAAAG ACGATAAGGGGAATACCCTGATTGTGAACAATCTGAACGGACTGTACGACAAAGATAATGACAAGCTG AAAAAGCTGATCAACAAAAGTCCCGAGAAGCTGCTGATGTACCACCATGATCCTCAGACATATCAGAA ACTGAAGCTGATTATGGAGCAGTACGGCGACGAGAAGAACCCACTGTATAAGTACTATGAAGAGACTG GGAACTACCTGACCAAGTATAGCAAAAAGGATAATGGCCCCGTGATCAAGAAGATCAAGTACTATGGG AACAAGOTGAATGCCCATCTGGACATCACAGACGATTACCCTAACAGTCGCAACAAGGTGGTCAAGCT GTCACTGAAGCCATACAGATTCGATGTCTATCTGGACAACGGCGTGTATAAATTTGTGACTGTCAAGA ATCTGGATGTCATCAAAAAGGAGAACTACTATGAAGTGAATAGCAAGTGCTACGAAGAGGCTAAAAAG CTGAAAAAGATTAGCAACCAGGCAGAGTTCATCGCCTCCTTTTACAACAACGACCTGATTAAGATCAA TGGCGAACTGTATAGGGTCATCGGGGTGAACAATGATCTGCTGAACCGCATTGAAGTGAATATGATTG ACATCACTTACCGAGAGTATCTGGAAAACATGAATGATAAGCGCCCCCCTCGAATTATCAAAACAATT GCCTCTAAGACTCAGAGTATCAAAAAGTACTCAACCGACATTCTGGGAAACCTGTATGAGGTGAAGAG CAAAAAGCACCCTCAGATTATCAAAAAGGGCagcggaggcaagcgtcctgctgctactaagaaagctg gtcaagctaagaaaaagaaaggatcctacccatacgatgttccagattacgcttaagaattcctagag ctcgctgatcagcctcgactgtgccttctagttgccagccatctgttgtttgcccctcccccgtgcct tccttgaccctggaaggtgccactcccactgtcctttcctaataaaatgaggaaattgcatcgcattg tctgagtaggtgtcattctattctggggggtggggtggggcaggacagcaagggggaggattgggaag agaatagcaggcatgctggggaggtagcggccgcCCgcggtggagctccagcttttgttccctttagt gagggttaattgcgcgcttggcgtaatcatggtcatagctgtttcctgtgtgaaattgttatccgctc acaattccacacaacatacgagccggaagcataaagtgtaaagcctggggtgcctaatgagtgagcta actcacattaattgcgttgcgctcactgcccgctttccagtcgggaaacctgtcgtgccagctgcatt aatgaatcggccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgctcact gactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggtt atccacagaatcaggggataacgcaggaaagaacatgtgagcaaaaggccagcaaaaggccaggaacc gtaaaaaggccgcgttgctggcgtttttccataggctccgcccccctgacgagcatcacaaaaatcga cgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtttccccctggaagctc cctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgcctttctcccttcgggaa gcgtggcgctttctcatagctcacgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctg ggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtc caacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggt atgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaaggacagtattt ggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaaca aaccaccgctggtagcggtggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctc aagaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggatt ttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatc aatctaaagtatatatgagtaaacttggtctgacagttaccaatgettaatcagtgaggcacctatct cagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacgatacgg gagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcaccggctccagattt atcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctcca tccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgtt gttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagctccggttc ccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctc cgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattct cttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaaccaagtcattctgaga atagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagca gaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctg ttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccag cgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaat gttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagc ggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagt gccac Target/ Spacer Sequence Guide # Original gRNA Cas9 (Sequence the gRNA targets and binds) nt First Round Screening: gAP1 Dyst (Intron51) SaCas9 CTTTACTTTGTATTATGTAAA 21 (SEQ ID NO: 29) gAP2 Dyst (Intron51) SaCas9 TTTGAAATATTTTTGATATCT 21 (SEQ ID NO: 30) gAP3 Dyst (Intron51) SaCas9 TTTAAGTAATCCGAGGTACTC 21 (SEQ ID NO: 31) gAP4 Dyst (Intron51) SaCas9 TTTAAATACATTGTCGTAATT 21 (SEQ ID NO: 32) 9AP5 Dyst (Intron51) SaCas9 TACCTTAATTTTGACGTCACA 21 (SEQ ID NO: 33) gAP6 Dyst (Intron51) SaCas9 ATTTGACAGGTGAGAAATCTC 21 (SEQ ID NO: 34) gAP7 Dyst (Intron51) SaCas9 TCATTTATAATACAGGGGAAT 21 (SEQ ID NO: 35) gAP8 Dyst (Intron51) SaCas9 TTAAAGTCATTTATAATACAG 21 (SEQ ID NO: 36) gAP9 Dyst (Intron51) SaCas9 AAATAGACACTGAAGAAAGGG 21 (SEQ ID NO: 37) gAP10 Dyst (Intron51) SaCas9 CCCCAATTAAAATAAAATTTA 21 (SEQ ID NO: 38) Second Round Screening: gAP11 g3 SaCas9 TAAGTAATCCGAGGTACTC 19 (SEQ ID NO: 39) gAP12 g3 SaCas9 TTAAGTAATCCGAGGTACTC 20 SEQ ID NO: 40) gAP13 g3 SaCas9 GTTTAAGTAATCCGAGGTACTC 22 (SEQ ID NO: 41) gAP14 g3 SaCas9 GGTTTAAGTAATCCGAGGTACTC 23 (SEQ ID NO: 42) gAP15 g6 SaCas9 TTGACAGGTGAGAAATCTC 19 (SEQ ID NO: 43) gAP16 g6 SaCas9 TTTGACAGGTGAGAAATCTC 20 (SEQ ID NO: 44) gAP17 g6 SaCas9 CATTTGACAGGTGAGAAATCTC 22 (SEQ ID NO: 45) gAP18 g6 SaCas9 TCATTTGACAGGTGAGAAATCTC 23 (SEQ ID NO: 46) gAP19 g7 SaCas9 ATTTATAATACAGGGGAAT 19 (SEQ ID NO: 47) gAP20 g7 SaCas9 CATTTATAATACAGGGGAAT 20 (SEQ ID NO: 48) gAP21 g7 SaCas9 GTCATTTATAATACAGGGGAAT 22 (SEQ ID NO: 49) gAP22 g7 SaCas9 AGTCATTTATAATACAGGGGAAT 23 (SEQ ID NO: 50) gAP23 scrambled SaCas9 GCACTACCAGAGCTAACTCA 20 (SEQ ID NO: 51) SEQ ID NO: 52 SaCas9 gRNA scaffold GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCTCGTCAACTTGT TGGCGAGA SEQ ID NO: 53 Exon 52 GCAACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTT GAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAA SEQ ID NO: 54 Donor sequence comprising exon 52 GTTAAATTGTTTTCTATAAACCCTTATACAGTAACATCTTTTTTATTTCTAAAAGTGTTTTGGCTGGT CTCACAATTGTACTTTACTTTGTATTATGTAAAAGGAATACACAACGOTGAAGAACCCTGATACTAAG GGATATTTGTTCTTACAGGCAACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCAT TACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAA GTAAGTTTTTTAACAAGCATGGGACACACAAAGCAAGATGCATGACAAGTTTCAATAAAAACTTAAGT TCATATATCCCCCTCACATTTATAAAAATAATGTGAAATAATTGTAAATGATAACAATTGTGCTGAGA TTTTCAGTCCATAATGTTACCTTTTAATAAATGAATGTAATTCCATTGAATAGAAGAAATAC SEQ ID NO: 55 Super exon (exons 52-79) GCAACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTT GAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATC AGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCA ACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTC ATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCA AAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGAT TATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCAT TCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCC TGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCT ACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCT CCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGATGAAAACAGCCAAAAAATCCTGA GATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGG AGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCG TCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGG CACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAA TTGAAAACTAAAGAACCTGTAATCATGAGTACTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCC TTTGGAAGGACTAGAGAAACTCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATG TCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCC GCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGA GCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCA TTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAG AACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAA CCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCA GGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAG GGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAAC TTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCT CAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTG TCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCA GATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCC CTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATC CGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATA CCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATG ATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGT GTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGAT GAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCA AGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAG CACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCA CTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTAC TAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAG ACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGC GCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGC TAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGAT GATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCG TAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAG ATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAA GGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGA GCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGG AAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCA GAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCA GCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTC CTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCA AGAGGAAGAAATACCOCTGGAAAGCCAATGAGAGAGGACACAATGTAG SEQ ID NO: 56 Donor sequence including super exon (exons 52-79) gTTAAtTTGcgTTCTAgccACCgagATACAGTAACATCTTTTTTATTTCTAAAAGTGTTTTGGCTGGT CTCACAATTGTACTTTACTTTGTATTATGTAAAAGGAATACACAACGOTGAAGAACCCTGATACTAAG GGATATTTGTTCTTACAGGCAACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCAT TACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAA TTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAAT GAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGC CAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAG AAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCC CTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAA TGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGAT TACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCC AATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGAT GAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGATGAAA ACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGAT AACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAG TTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATG ATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACAT AGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTACTCTTGAGACTGTACGAAT ATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACTCTACCAGGAGCCCAGAGAGCTGCCTCCTG AGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAA AAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACT TCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGC CCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAA ATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCAT TCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGG CCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTT CTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAA CCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACC TGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGC TTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCA GCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACA ACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACG GGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTT GGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGC TGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGC AGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGC CCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGG CTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTC AGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGC AAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTC GAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATG GGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTT CTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTG AACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCT CCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTC CCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGC TAGAGAGAATCCTAGCAGATOTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAG CAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCA GAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAG CCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTG CTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACA GAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTG AGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAAC AACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAG TC GTTTAAACCGCTGATCAGCCTCGAAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAG CATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCA ATGTATCTTAGTAAGTTTTTTAACAAGCATGGGACACACAAAGCAAGATGCATGACAAGTTTCAATAA AAACTTAAGTTCATATATCCCCCTCACATTTATAAAAATAATGTGAAATAATTGTAAATGATAACAAT TGTGCTGAGATTTTCAGTCCATAATGTTACCTTTTAATAAATGAATGTAATTCCATTGAATAGAAGAA ATAC SEQ ID NO: 57 AAV expression cassette for version 1 exon52 donor sequence with gRNA7: AAV ITR, U6 PROMOTER, 

  PAM (ATTCCT) , SaCas9 gRNA SCAFFOLD, donor sequence, exon52 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCG ACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCA ACTCCATCACTAGGGGTTCCTCAGATCTGAATTCGGTACCTTCCTAGGGCCTATTTCCCATG ATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATAATTGGAATTAATTTGAC TGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTAATAATTTCTTGGGTAGT TTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTAT TTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACCG 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCT CGTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGTACAAAGTTGGCGTTTAA AC 

gttaaattgttttctataaacccttatacagta acatcttttttatttctaaaagtgttttggctggtctcacaattgtactttactttgtatta tgtaaaaggaatacacaacgctgaagaaccctgatactaagggatatttgttcttacaggca acaatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgctgcccaaaa tttgaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaagtaagtttt ttaacaagcatgggacacacaaagcaagatgcatgacaagtttcaataaaaacttaagttca tatatccccctcacatttataaaaataatgtgaaataattgtaaatgataacaattgtgctg agattttcagtccataatgttaccttttaataaatgaatgtaattccattgaatagaagaaa tac ATTCCT  

GCTAGCTCGGAGAGACGACATCTAGAATTAAA CTGTCACTATCGATTACTAATTTTTTGCTCATAATAGAAGCAGCGATTAAAGGAATAGAATC AACAGTTCCAGTAACATCTCTTAGTGCATACATTTTTTTATCAGCAGGAACAATATCATCTG ACTGACCTGTGATGCTCATTCCAACTTCATTAATTGTTTTAATGAATTTTTCTTTAGATAAT TCACTTGTTCAACCTTTACATGACTCTAATTTATCAATAGTACCACCAGTTACTCCAAGTCC TCTACCAGAAAGTTTACAAACCTTTACTCCATAACTTGCAACTAACGGACTATATACTAAAC TTGTTTTGTCTCCAACTCCGCCAGTTGAATGCTTATCAGCTTTTAAACCTGTAACCTCACTG ACATCATAAACATATCCTGATTCAACATAAGATTGGGTTAATGCTAAAGTTTCTGCTTTGGT CATTCCATTAAAATAAACCGCCATAGCAAAAGCAGCCATTTGATAATCTGTTACATTATTTT TAACGTAACTGTTTATCAATCATTTAATTTCTTCAGCTGATAATTCTATTGAATGTTTCTTT TTTTCTATAATTTCACTAAAACTGTAGTTCATAAGTCTCCTTTTGTAAGAGTGCACAATATT TACACCATTACTCTTTCTACTATATTATAATAGAATAGACATATAAAAAACATAAGGAGTAC AAATGGTTTTTGATAAAAATAACAAAGTTTATAGTGAATGAATAAATAGCCAAAAATTGGAT GATGAGTTGAAAAGCCTTTTAGTAAATGCTACTGATGATGAATTGCATGCAGCATTTGAAGG AATAGAGTTAGAATTTGGAACAGCAGGTATAAGAGGTATTCTTGGAGCAGGACCTGGAAGAT TTAACGTTTACACTGTTAAAAAAGTTACTATTGCATTTGCAGAATTATTAAAACAAAATTAC CCAAATAGGTTGAATGATGGAATAGTTGTTGGTCATGATAACCGTCATAATTCTAAACAGTT TGCAAAAGTTGTAGCCGAAGTTTTATCAAGCTTGTGAAATAGCTGTTGAAGCTGGATTAGAA TTTGTTAAAACATCAACAGGATTTTCAAAATCAGGTGCAACATTTGAAGATGTTAAACTAAT GAAGTCAGTTGTTAAAGACAATGOTTTAGTTAAAGCAGCTGGTGGAGTTAGAACATTTGAAG ATGCTCAAAAAATGATTGAAGCAGGAGCTGACCGCTTAGGAACAAGTGGTGGAGTAGCTATT ATTAAAGGTGAAGAAAACAACGCGAGTTACTAAAACTAGCGTTTTTTTATTTTGCTCATTTT TATTAAAAGTTTGCAAAAAGGAACATAAAAATTCTAATTATTGATACTAAAGTTATTAAAAA GAAGATTTTGGTTGATTTTATAAAGGTCATAGAATATAATATTTTAGCATGTGTATTTTGTG TGCTCATTTACAACCGTCTCGCGGCCGCGGGGATCCAGACATGATAAGATACATTGATGAGT TTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCT ATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCA TTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAGTCGACCTCGAGCAGTGTGG TTTTGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCACCCAAGTCGAA GGCAGTGTGGTTTTGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCAC CCAATGTCGAGCAACCCCGCCCAGCGTCTTGTCATTGGCGAATTCGAACACGCAGATGCAGT CGGGGCGGCGCGGTCCCAGGTCCACTTCGCATATTAAGGTGACGCGTGTGGCCTCGAACACC GAGCGACCCTGCAGCCAATATGGGATCGGCCATTGAACAAGATGGATTGCACGCAGGTTCTC CGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCT GATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCT GTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGG GCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTG GGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCAT CATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACC AAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGAT GATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCG CATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGG TGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTAT CAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCG CTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTC TTGACGAGTTCTTCTGAGGGGATCCGTCGACTAGAGCTCGCTGATCAGCCTCGACTGTGCCT TCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGC CACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTC ATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGC AGGCATGCTGGGGAGAGATCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGC GCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCC GGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAA SEQ ID NO: 58 AAV expression cassette for version 1 exon52 donor sequence with gRNA12: AAV ITR, U6 PROMOTER, 

  PAM , SaCas9 gRNA SCAFFOLD, donor sequence, exon52 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCG ACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCA ACTCCATCACTAGGGGTTCCTCAGATCTGAATTCGGTACCTTCCTAGGGCCTATTTCCCATG ATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATAATTGGAATTAATTTGAC TGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTAATAATTTCTTGGGTAGT TTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTAT TTCGATTTOTTGGCTTTATATATCTTGTGGAAAGGACGAAACACCG 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCTC GTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGTACAAAGTTGGCGTTTAAA C 

gttaaattgttttctataaacccttatacagtaac atcttttttatttctaaaagtgttttggctggtctcacaattgtactttactttgtattatg taaaaggaatacacaacgctgaagaaccctgatactaagggatatttgttcttacaggcaac aatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgctgcccaaaatt tgaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaagtaagtttttt aacaagcatgggacacacaaagcaagatgcatgacaagtttcaataaaaacttaagttcata tatccccctcacatttataaaaataatgtgaaataattgtaaatgataacaattgtgctgag attttcagtccataatgttaccttttaataaatgaatgtaattccattgaatagaagaaata C 

GCTAGCTCGGAGAGACGACATCTAGAATTAAACTG TCACTATCGATTACTAATTTTTTGCTCATAATAGAAGCAGCGATTAAAGGAATAGAATCAAC AGTTCCAGTAACATCTCTTAGTGCATACATTTTTTTATCAGCAGGAACAATATCATCTGACT GACCTGTGATGCTCATTCCAACTTCATTAATTGTTTTAATGAATTTTTCTTTAGATAATTCA CTTGTTCAACCTTTACATGACTCTAATTTATCAATAGTACCACCAGTTACTCCAAGTCCTCT ACCAGAAAGTTTACAAACCTTTACTCCATAACTTGCAACTAACGGACTATATACTAAACTTG TTTTGTCTCCAACTCCGCCAGTTGAATGCTTATCAGCTTTTAAACCTGTAACCTCACTGACA TCATAAACATATCCTGATTCAACATAAGATTGGGTTAATGCTAAAGTTTCTGCTTTGGTCAT TCCATTAAAATAAACCGCCATAGCAAAAGCAGCCATTTGATAATCTGTTACATTATTTTTAA CGTAACTGTTTATCAATCATTTAATTTCTTCAGCTGATAATTCTATTGAATGTTTCTTTTTT TCTATAATTTCACTAAAACTGTAGTTCATAAGTCTCCTTTTGTAAGAGTGCACAATATTTAC ACCATTACTCTTTCTACTATATTATAATAGAATAGACATATAAAAAACATAAGGAGTACAAA TGGTTTTTGATAAAAATAACAAAGTTTATAGTGAATGAATAAATAGCCAAAAATTGGATGAT GAGTTGAAAAGCCTTTTAGTAAATGCTACTGATGATGAATTGCATGCAGCATTTGAAGGAAT AGAGTTAGAATTTGGAACAGCAGGTATAAGAGGTATTCTTGGAGCAGGACCTGGAAGATTTA ACGTTTACACTGTTAAAAAAGTTACTATTGCATTTGCAGAATTATTAAAACAAAATTACCCA AATAGGTTGAATGATGGAATAGTTGTTGGTCATGATAACCGTCATAATTCTAAACAGTTTGC AAAAGTTGTAGCCGAAGTTTTATCAAGCTTGTGAAATAGCTGTTGAAGCTGGATTAGAATTT GTTAAAACATCAACAGGATTTTCAAAATCAGGTGCAACATTTGAAGATGTTAAACTAATGAA GTCAGTTGTTAAAGACAATGCTTTAGTTAAAGCAGCTGGTGGAGTTAGAACATTTGAAGATG CTCAAAAAATGATTGAAGCAGGAGCTGACCGCTTAGGAACAAGTGGTGGAGTAGCTATTATT AAAGGTGAAGAAAACAACGCGAGTTACTAAAACTAGCGTTTTTTTATTTTGCTCATTTTTAT TAAAAGTTTGCAAAAAGGAACATAAAAATTCTAATTATTGATACTAAAGTTATTAAAAAGAA GATTTTGGTTGATTTTATAAAGGTCATAGAATATAATATTTTAGCATGTGTATTTTGTGTGC TCATTTACAACCGTCTCGCGGCCGCGGGGATCCAGACATGATAAGATACATTGATGAGTTTG GACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATT GCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTT TATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAGTCGACCTCGAGCAGTGTGGTTT TGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCACCCAAGTCGAAGGC AGTGTGGTTTTGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCACCCA ATGTCGAGCAACCCCGCCCAGCGTCTTGTCATTGGCGAATTCGAACACGCAGATGCAGTCGG GGCGGCGCGGTCCCAGGTCCACTTCGCATATTAAGGTGACGCGTGTGGCCTCGAACACCGAG CGACCCTGCAGCCAATATGGGATCGGCCATTGAACAAGATGGATTGCACGCAGGTTCTCCGG CCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGAT GCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTC CGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCG TTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGC GAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCAT GGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAG CGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGAT CTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCAT GCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGG AAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAG GACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTT CCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTG ACGAGTTCTTCTGAGGGGATCCGTCGACTAGAGCTCGCTGATCAGCCTCGACTGTGCCTTCT AGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCAC TCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATT CTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGG CATGCTGGGGAGAGATCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCT CGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGC CTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAA SEQ ID NO: 59 AAV expression cassette for version 2 exon52 donor sequence with gRNA7: *Note: version 2 is referring to modified donor sequence for improved detection via deep sequencing analysis (these modified nucleotides are provided in lowercase) AAV ITR, U6 PROMOTER, 

  PAM (ATTCCT) , SaCas9 gRNA SCAFFOLD, donor sequence, exon52 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCG ACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCA ACTCCATCACTAGGGGTTCCTCAGATCTGAATTCGGTACCTTCCTAGGGCCTATTTCCCATG ATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATAATTGGAATTAATTTGAC TGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTAATAATTTCTTGGGTAGT TTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTAT TTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACCG 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCT CGTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGTACAAAGTTGGCGTTTAA AC 

gttaatttgcgttctagccaccgagatacagta acatcttttttatttctaaaagtgttttggctggtctcacaattgtactttactttgtatta tgtaaaaggaatacacaacgctgaagaaccctgatactaagggatatttgttcttacaggca acaatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgctgcccaaaa tttgaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaagtaagtttt ttaacaagcatgggacacacaaagcaagatgcatgacaagtttcaataaaaacttaagttca tatatccccctcacatttataaaaataatgtgaaataattgtaaatgataacaattgtgctg agattttcagtccataatgttaccttttaataaatgaatgtaattccattgaatagaagaaa tac 

GCTAGCTCGGAGAGACGACATCTAGAATTAAA CTGTCACTATCGATTACTAATTTTTTGCTCATAATAGAAGCAGCGATTAAAGGAATAGAATC AACAGTTCCAGTAACATCTCTTAGTGCATACATTTTTTTATCAGCAGGAACAATATCATCTG ACTGACCTGTGATGCTCATTCCAACTTCATTAATTGTTTTAATGAATTTTTCTTTAGATAAT TCACTTGTTCAACCTTTACATGACTCTAATTTATCAATAGTACCACCAGTTACTCCAAGTCC TCTACCAGAAAGTTTACAAACCTTTACTCCATAACTTGCAACTAACGGACTATATACTAAAC TTGTTTTGTCTCCAACTCCGCCAGTTGAATGCTTATCAGCTTTTAAACCTGTAACCTCACTG ACATCATAAACATATCCTGATTCAACATAAGATTGGGTTAATGCTAAAGTTTCTGCTTTGGT CATTCCATTAAAATAAACCGCCATAGCAAAAGCAGCCATTTGATAATCTGTTACATTATTTT TAACGTAACTGTTTATCAATCATTTAATTTCTTCAGCTGATAATTCTATTGAATGTTTCTTT TTTTCTATAATTTCACTAAAACTGTAGTTCATAAGTCTCCTTTTGTAAGAGTGCACAATATT TACACCATTACTCTTTCTACTATATTATAATAGAATAGACATATAAAAAACATAAGGAGTAC AAATGGTTTTTGATAAAAATAACAAAGTTTATAGTGAATGAATAAATAGCCAAAAATTGGAT GATGAGTTGAAAAGCCTTTTAGTAAATGCTACTGATGATGAATTGCATGCAGCATTTGAAGG AATAGAGTTAGAATTTGGAACAGCAGGTATAAGAGGTATTCTTGGAGCAGGACCTGGAAGAT TTAACGTTTACACTGTTAAAAAAGTTACTATTGCATTTGCAGAATTATTAAAACAAAATTAC CCAAATAGGTTGAATGATGGAATAGTTGTTGGTCATGATAACCGTCATAATTCTAAACAGTT TGCAAAAGTTGTAGCCGAAGTTTTATCAAGCTTGTGAAATAGCTGTTGAAGCTGGATTAGAA TTTGTTAAAACATCAACAGGATTTTCAAAATCAGGTGCAACATTTGAAGATGTTAAACTAAT GAAGTCAGTTGTTAAAGACAATGOTTTAGTTAAAGCAGCTGGTGGAGTTAGAACATTTGAAG ATGCTCAAAAAATGATTGAAGCAGGAGCTGACCGCTTAGGAACAAGTGGTGGAGTAGCTATT ATTAAAGGTGAAGAAAACAACGCGAGTTACTAAAACTAGCGTTTTTTTATTTTGCTCATTTT TATTAAAAGTTTGCAAAAAGGAACATAAAAATTCTAATTATTGATACTAAAGTTATTAAAAA GAAGATTTTGGTTGATTTTATAAAGGTCATAGAATATAATATTTTAGCATGTGTATTTTGTG TGCTCATTTACAACCGTCTCGCGGCCGCGGGGATCCAGACATGATAAGATACATTGATGAGT TTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCT ATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGITAACAACAACAATTGCATTCA TTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAGTCGACCTCGAGCAGTGTGG TTTTGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCACCCAAGTCGAA GGCAGTGTGGTTTTGCAAGAGGAAGCAAAAAGCCTCTCCACCCAGGCCTGGAATGTTTCCAC CCAATGTCGAGCAACCCCGCCCAGCGTCTTGTCATTGGCGAATTCGAACACGCAGATGCAGT CGGGGCGGCGCGGTCCCAGGTCCACTTCGCATATTAAGGTGACGCGTGTGGCCTCGAACACC GAGCGACCCTGCAGCCAATATGGGATCGGCCATTGAACAAGATGGATTGCACGCAGGTTCTC CGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCT GATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCT GTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGG GCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTG GGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCAT CATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACC AAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGAT GATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCG CATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGG TGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTAT CAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCG CTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTC TTGACGAGTTCTTCTGAGGGGATCCGTCGACTAGAGCTCGCTGATCAGCCTCGACTGTGCCT TCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGC CACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTC ATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGC AGGCATGCTGGGGAGAGATCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGC GCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCC GGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAA SEQ ID NO: 60 AAV expression cassette for superexon (exon52-exon79) donor sequence with gRNA7: *Note: version 2 is referring to modified donor sequence for improved detection via deep sequencing analysis (these modified nucleotides are provided in lowercase) AAV ITR, U6 PROMOTER, 

  PAM (AATCCT) , SaCas9 gRNA SCAFFOLD, donor sequence, exon52-79 cDNA sequence, 

TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCG ACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCA ACTCCATCACTAGGGGTTCCTCAGATCTGAATTCGGTACCTTCCTAGGGCCTATTTCCCATG ATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATAATTGGAATTAATTTGAC TGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTAATAATTTOTTGGGTAGT TTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTACCGTAACTTGAAAGTAT TTCGATTTOTTGGCTTTATATATCTTGTGGAAAGGACGAAACACCG 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCAAAATGCCGTGTTTATCT CGTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGTACAAAGTTGGCGTTTAA AC 

gttaatttgcgttctagccaccgagatacagta acatcttttttatttctaaaagtgttttggctggtctcacaattgtactttactttgtatta tgtaaaaggaatacacaacgctgaagaaccctgatactaagggatatttgttcttacaggca acaatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgctgcccaaaa tttgaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaattgaaagaa ttcagaatcagtgggatgaagtacaagaacaccttcagaaccggaggcaacagttgaatgaa atgttaaaggattcaacacaatggctggaagctaaggaagaagctgagcaggtcttaggaca ggccagagccaagcttgagtcatggaaggagggtccctatacagtagatgcaatccaaaaga aaatcacagaaaccaagcagttggccaaagacctccgccagtggcagacaaatgtagatgtg gcaaatgacttggccctgaaacttctccgggattattctgcagatgataccagaaaagtcca catgataacagagaatatcaatgcctcttggagaagcattcataaaagggtgagtgagcgag aggctgctttggaagaaactcatagattactgcaacagttccccctggacctggaaaagttt cttgcctggcttacagaagctgaaacaactgccaatgtcctacaggatgctacccgtaagga aaggctcctagaagactccaagggagtaaaagagctgatgaaacaatggcaagacctccaag gtgaaattgaagctcacacagatgtttatcacaacctggatgaaaacagccaaaaaatcctg agatccctggaaggttccgatgatgcagtcctgttacaaagacgtttggataacatgaactt caagtggagtgaacttcggaaaaagtctctcaacattaggtcccatttggaagccagttctg accagtggaagcgtctgcacctttctctgcaggaacttctggtgtggctacagctgaaagat gatgaattaagccggcaggcacctattggaggcgactttccagcagttcagaagcagaacga tgtacatagggccttcaagagggaattgaaaactaaagaacctgtaatcatgagtactcttg agactgtacgaatatttctgacagagcagcctttggaaggactagagaaactctaccaggag cccagagagctgcctcctgaggagagagcccagaatgtcactcggcttctacgaaagcaggc tgaggaggtcaatactgagtgggaaaaattgaacctgcactccgctgactggcagagaaaaa tagatgagacccttgaaagactccaggaacttcaagaggccacggatgagctggacctcaag ctgcgccaagctgaggtgatcaagggatcctggcagcccgtgggcgatctcctcattgactc tctccaagatcacctcgagaaagtcaaggcacttcgaggagaaattgcgcctctgaaagaga acgtgagccacgtcaatgaccttcctcgccagcttaccactttgggcattcagctctcaccg tataacctcagcactctggaagacctgaacaccagatggaagcttctgcaggtggccgtcga ggaccgagtcaggcagctgcatgaagcccacagggactttggtccagcatctcagcactttc tttccacgtctgtccagggtccctgggagagagccatctcgccaaacaaagtgccctactat atcaaccacgagactcaaacaacttgctgggaccatcccaaaatgacagagctctaccagtc tttagctgacctgaataatgtcagattctcagcttataggactgccatgaaactccgaagac tgcagaaggccctttgcttggatctcttgagcctgtcagctgcatgtgatgccttggaccag cacaacctcaagcaaaatgaccagcccatggatatcctgcagattattaattgtttgaccac tatttatgaccgcctggagcaagagcacaacaatttggtcaacgtccctctctgcgtggata tgtgtctgaactggctgctgaatgtttatgatacgggacgaacagggaggatccgtgtcctg tcttttaaaactggcatcatttccctgtgtaaagcacatttggaagacaagtacagatacct tttcaagcaagtggcaagttcaacaggattttgtgaccagcgcaggctgggcctccttctgc atgattctatccaaattccaagacagttcggtgaagttgcatcctttgggggcagtaacatt gagccaagtgtccggagctgcttccaatttgctaataataagccagagatcgaagcggccct cttcctagactcgatgagactggaaccccagtccatggtgtggctgcccgtcctgcacagag tggctgctgcagaaactgccaagcatcaggccaaatgtaacatctgcaaagagtgtccaatc attggattcaggtacaggagtctaaagcactttaattatgacatctgccaaagctgcttttt ttctggtcgagttgcaaaaggccataaaatgcactatcccatggtggaatattgcactccga ctacatcaggagaagatgttcgagactttgccaaggtactaaaaaacaaatttcgaaccaaa aggtattttgcgaagcatccccgaatgggctacctgccagtgcagactgtcttagaggggga caacatggaaactcccgttactctgatcaacttctggccagtagattctgcgcctgcctcgt cccctcagctttcacacgatgatactcattcacgcattgaacattatgctagcaggctagca gaaatggaaaacagcaatggatcttatctaaatgatagcatctctcctaatgagagcataga tgatgaacatttgttaatccagcattactgccaaagtttgaaccaggactcccccctgagcc agcctcgtagtcctgcccagatcttgatttccttagagagtgaggaaagaggggagctagag agaatcctagcagatcttgaggaagaaaacaggaatctgcaagcagaatatgaccgtctaaa gcagcagcacgaacataaaggcctgtccccactgccgtcccctcctgaaatgatgcccacct ctccccagagtccccgggatgctgagctcattgctgaggccaagctactgcgtcaacacaaa ggccgcctggaagccaggatgcaaatcctggaagaccacaataaacagctggagtcacagtt acacaggctaaggcagctgctggagcaaccccaggcagaggccaaagtgaatggcacaacgg tgtcctctccttctacctctctacagaggtccgacagcagtcagcctatgctgctccgagtg gttggcagtcaaacttcggactccatgggtgaggaagatcttctcagtcctccccaggacac aagcacagggttagaggaggtgatggagcaactcaacaactccttccctagttcaagaggaa gaaatacccctggaaagccaatgagagaggacacaatg 

tcagc ctcga 

 

 

 

 

gtaagttttttaacaagcatgggacacacaaagcaagatgcatgacaagtttcaataaa aacttaagttcatatatccccctcacatttataaaaataatgtgaaataattgtaaatgata acaattgtgctgagattttcagtccataatgttaccttttaataaatgaatgtaattccatt gaatagaagaaatac 

CGGCCGGAAGACAATAGCAG GCATGCTGGGGAGAGATCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGC TCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGG CCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAA SEQ ID NO: 61 SV40 NLS Pro-Lys-Lys-Lys-Arg-Lys-Val SEQ ID NO: 62 DNA sequence of the gRNA constant region gtttaagagctatgctggaaacagcatagcaagtttaaataaggctagtccgttatcaactt gaaaaagtggcaccgagteggtgc SEQ ID NO: 63 RNA sequence of the gRNA constant region guuuaagagcuaugcuggaaacagcauagcaaguuuaaauaagguaguccguuaucaacuu gaaaaaguggcaccgagucggugc Spacer Sequence (Sequence the gRNA targets and binds) PAM gRNA gScb GCACTACCAGAGCTAACTCA NNGRRT GCACUACCAGAGCUAACUCA (SEQ ID NO: 87) (SEQ ID (SEQ ID NO: 88) NO: 9) g1 CTTTACTTTGTATTATGTAAA AGGAAT CUUUACUUUGUAUUAUGUAAA (SEQ ID NO: 29) (SEQ ID (SEQ ID NO: 64) NO: 89) g2 TTTGAAATATTTTTGATATCT AAGAAT UUUGAAAUAUUUUUGAUAUCU (SEQ ID NO: 30) (SEQ ID (SEQ ID NO: 65) NO: 90) g3 TTTAAGTAATCCGAGGTACTC CGGAAT UUUAAGUAAUCCGAGGUACUC (SEQ ID NO: 31) (SEQ ID (SEQ ID NO: 66) NO: 91) g4 TTTAAATACATTGTCGTAATT CAGAAT UUUAAAUACAUUGUCGUAAUU (SEQ ID NO: 32) (SEQ ID (SEQ ID NO: 67) NO: 92) g5 TACCTTAATTTTGACGTCACA CAGAAT UACCUUAAUUUUGACGUCACA (SEQ ID NO: 33) (SEQ ID (SEQ ID NO: 68) NO: 92) g6 ATTTGACAGGTGAGAAATCTC AGGGGT AUUUGACAGGUGAGAAAUCUC (SEQ ID NO: 34) (SEQ ID (SEQ ID NO: 69) NO: 93) g7 TCATTTATAATACAGGGGAAT AGGAAT UCAUUUAUAAUACAGGGGAAU (SEQ ID NO: 35) (SEQ ID (SEQ ID NO: 70) NO: 89) g8 TTAAAGTCATTTATAATACAG GGGAAT UUAAAGUCAUUUAUAAUACAG (SEQ ID NO: 36) (SEQ ID (SEQ ID NO: 71) NO: 94) g9 AAATAGACACTGAAGAAAGGG AAGAAT AAAUAGACACUGAAGAAAGGG (SEQ ID NO: 37) (SEQ ID (SEQ ID NO: 72) NO: 90) g10 CCCCAATTAAAATAAAATTTA CTGAGT CCCCAAUUAAAAUAAAAUUUA (SEQ ID NO: 38) (SEQ ID (SEQ ID NO: 73) NO: 95) g11 TAAGTAATCCGAGGTACTO CGGAAT UAAGUAAUCCGAGGUACUC (g3) (SEQ ID NO: 39) (SEQ ID (SEQ ID NO: 74) NO: 91) g12 TTAAGTAATCCGAGGTACTC CGGAAT UUAAGUAAUCCGAGGUACUC (g3) (SEQ ID NO: 40) (SEQ ID (SEQ ID NO: 75) NO: 91) g13 GTTTAAGTAATCCGAGGTACT CGGAAT GUUUAAGUAAUCCGAGGUAC (g3) C (SEQ ID UC (SEQ ID NO: 41) NO: 91) (SEQ ID NO: 76) g14 GGTTTAAGTAATCCGAGGTAC CGGAAT GGUUUAAGUAAUCCGAGGUA (g3) TC (SEQ ID CUC (SEQ ID NO: 42) NO: 91) (SEQ ID NO: 77) g15 TTGACAGGTGAGAAATCTC AGGGGT UUGACAGGUGAGAAAUCUC (g6) (SEQ ID NO: 43) (SEQ ID (SEQ ID NO: 78) NO: 93) g16 TTTGACAGGTGAGAAATCTC AGGGGT UUUGACAGGUGAGAAAUCUC (g6) (SEQ ID NO: 44) (SEQ ID (SEQ ID NO: 79) NO: 93) g17 CATTTGACAGGTGAGAAATCT AGGGGT CAUUUGACAGGUGAGAAAUCU (g6) C (SEQ ID C (SEQ ID NO: 45) NO: 93) (SEQ ID NO: 80) g18 TCATTTGACAGGTGAGAAATC AGGGGT UCAUUUGACAGGUGAGAAAUC (g6) TC (SEQ ID UC (SEQ ID NO: 46) NO: 93) (SEQ ID NO: 81) g19 ATTTATAATACAGGGGAAT AGGAAT AUUUAUAAUACAGGGGAAU (g7) (SEQ ID NO: 47) (SEQ ID (SEQ ID NO: 82) NO: 89) g20 CATTTATAATACAGGGGAAT AGGAAT CAUUUAUAAUACAGGGGAAU (g7) (SEQ ID NO: 48) (SEQ ID (SEQ ID NO: 83) NO: 89) g21 GTCATTTATAATACAGGGGAA AGGAAT GUCAUUUAUAAUACAGGGGAA (g7) T (SEQ ID U (SEQ ID NO: 49) NO: 89) (SEQ ID NO: 84) g22 AGTCATTTATAATACAGGGGA AGGAAT AGUCAUUUAUAAUACAGGGGA (g7) AT (SEQ ID AU (SEQ ID NO: 50) NO: 89) (SEQ ID NO: 85) g23 GCACTACCAGAGOTAACTCA GCACUACCAGAGCUAACUCA (SEQ ID NO: 51) (SEQ ID NO: 86) SEQ ID NO: 96 gRNA targeting human intron 51 CTCTGATAACCCAGCTGTGTGTT SEQ ID NO: 97 gRNA targeting human intron 52 CTAGACCATTTOCCACCAGTTCT Description Forward Primer (5′-3′) Surveyor Fwd: CTGATGCTCTCCAAACTTGCC (SEQ ID NO: 98) (g1, g5, g6) Rev: TGCTTTGTGTGTCCCATGCT (SEQ ID NO: 99) Surveyor Fwd: ATACCTCTGAGATTGTGGTCCT (SEQ ID NO: 100) (g2, g3, g4) Rev: TGGGCAGCGGTAATGAGTTC (SEQ ID NO: 101) Surveyor Fwd: TTACTGAGTTTTAGAACCAGAGCTA (SEQ ID NO: 102) (g7, g8) Rev: AGGGTTCTTCAGCGTTGTGT (SEQ ID NO: 103) Surveyor Fwd: AGCAGGAGTCAAAGTACAGAGT (SEQ ID NO: 104) (g9, g10) Rev: TCCGGAGTACCTCGGATTAC (SEQ ID NO: 105) gDNA integration Fwd: TTACTGAGTTTTAGAACCAGAGCTA (SEQ ID NO: 106) PCR Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 107) CDNA integration Fwd: CTGACCACTATTGGAGCCTCTC (SEQ ID NO: 108) PCR Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 109) 3′ RACE GSP GTAGTCGTTTAAACCGCTGATCAGCCTCG (SEQ ID NO: 110) ddPCR - Corrected Fwd: GCTTTCTCTGCTTGATCAAG (SEQ ID NO: 111) (Ex51-Ex52 junction) Rev: GAGTTCTTCCAACTGGGGAC (SEQ ID NO: 112) Probe: GCAACAATGCAGGATTTG (SEQ ID NO: 113) ddPCR - Unedited Fwd: GCTTTCTCTGCTTGATCAAG (SEQ ID NO: 114) (Ex51-Ex53 junction) Rev: CGGTTCTGAAGGTGTTCTTGTA (SEQ ID NO: 115) Probe: AGCAGAAGTTGAAAG (SEQ ID NO: 116) ddPCR Fwd: GATGAGCTGGACCTCAAGCT (SEQ ID NO: 117) Normalization Rev: GTGGCTCACGTTCTCTTTCA (SEQ ID NO: 118) (Ex59-Ex60 junction) Probe: CGAGAAAGTCAAGGCACT (SEQ ID NO: 119) Tn5-Top CAAGCAGAAGACGGCATACGAGATNNNNNNNNNNGTCTCGTGGG CTCGGAGATGTGTATAAGAGACAG (SEQ ID NO: 120) Tn5-Bottom [Phos]CTGTCTCTTATACACATCT (SEQ ID NO: 121) Tn5-GSP (g7) AAGCAGTGGTATCAACGCAGAGTACCAGAGAAAATAGACACTGA AGAAAGGG (SEQ ID NO: 122) Tn5-GSP (g12) AAGCAGTGGTATCAACGCAGAGTACCOTTAATTTTGACGTCACAC AGAATG (SEQ ID NO: 123) Tn5-Universal CAAGCAGAAGACGGCATACGAGAT (SEQ ID NO: 124) Tn5-BC, [i5 barcode] AATGATACGGCGACCACCGAGATCTACAC[NNNNNNJCGGAAGCA GTGGTATCAACGCAGAGTAC (SEQ ID NO: 125) Tn5-Read1 CGGAAGCAGTGGTATCAACGCAGAGTAC (SEQ ID NO: 126) (Miseq/Novaseq) Tn5-Index1 GTACTCTGCGTTGATACCACTGCTTCCG (SEQ ID NO: 127) (Novaseq) SEQ ID NO: 128 Intron 51 of the human dystrophin gene GTATGAGAAAAAATGATAAAAGTTGGCAGAAGTTTTTCTTTAAAATGAAGATTTTCCACCAATCACTT TACTCTCCTAGACCATTTCCCACCAGTTCTTAGGCAACTGTTTCTCTCTCAGCAAACACATTACTCTC ACTATTCAGCCTAAGTATAATCAAGGATATAAATTAATGCAAATAACAAAAGTAGCCATACATTAAAA AGGAAATATACAAAAAAAAAAAAAAAAAAAGCAGAAACCTTACAAGAATAGTTGTCCTCAGTTAAATT TACTAAACAACCTGGTATTTTAAAAATCTATTTTATACCAAATAAGTCACTCAACTGAGCTATTTACA TTTAAACTGTTTGTTTTGGCACTACGCAGCCCAACATATTGCAGAATCAAATATAATAGTCTGGGAAT TGATTATTATCCACTCTTCTAAGTTGTCTGTGCCAATTTGCCTTCTCCAATGATAAGGATAATTGAAA GAGAGCTATAACTTAAAAAGAGAAAAGTAACAAAACATAAGATATTTAAAATTACCCTAGATCTTAAA GTTGGCATTTATGCAATGCCATGTTCAAATGAACATGTTTTTAATACAAATAGTGCATTTTTCAGCCT CAGTGTAATCCATTTGGTAAAATTATGACATCAACTAGAAACATTAGAATACATTGATGTAAATATGG TTTACCTAGCTAGATCAAATATACTATATATCTTTTATATTTGTGAATGATTAAGAAAAATAATGTTG GAATTGTTATACATTAAAGTTTTTTCACTTGTAACAGCTTTCAAGCCTTTCTAAAGAAATACAAAGTT GTGCTGAAGGTATTTAGGTATTAAAGTACTACCTTTTGAAAAAACAAGAAGTGAGGCAGACAGAGTAA GGGGAATTTCTTTGTAAAATAAACTTCACCAATTCCATAGGAATAAAAGTAATTTGATAGTAAACAAC CTGCATTTAAAGGCCTTGAGCTTGAATACAGAAGACCTGAATTCAGTGCCATTTGCAAATGATGATTG TGGTCAAGCCATCTCTGGATCTTCGTTTCCTATTCTGAGTACAGAGCATACAGAGTACACATTCACAT TCACAATATAGTTATGGATATGGATGTATATAAATATATGTAAATACTACATATATGTACCTAAAATT TGTTTTACTTCTGCTTTAAAAAAAGTAATTATAGCCACATTTTTCAGAAAAAGTAACTGAGGCTCATA GATGTCAAATTCCCAGTAAGTAGCAGAACAAGGATTCAAATCCAAGTCCATTTGATTCCTAAGCTTGT GTTATTACTTGCTACTGCAGAGAGTATACGTAGCAAGTAATATATGTACTGCAAGCAATACATACTAT TGCTGCGGTAATAACTGTAACTGCAGTTACTATTTAGTGATTTGTATGTAGATGTAGATGTAGTCTAT GTCAGACACTATGCTGAGCATTTTATGGTTGCTATGTACTGATACATACAGAAACAAGAGGTACGTTC TTTTACAATACCATATTGAGTTATATAATACTCCCAGGACTTTTATTTACCAAAGGAAACAATATTTT ATAATGTTTAAAGCCCAGGTTTTGAAGTTACATTGTCTGGGTTCAAAGCTTGGCTCCCAAGCTGTGTG ACCTTGAGTAAGTTATTCTGCCTACCTGAGCCCAAGTTTATCTAGCTATAAAATGGGGATAGTTGTAC TATCTGCCTTGCAGTTTGTCATCAGGATTAAGTTGGTTGGTACATGAAAAATGCTTCCCACTTTGCCT TGCTTACTGCTTACTGCTAGTATTGAACAAATGTTAGTAATTATATTTGGTTCCACCACGAACTCTAG AAATCTAACCAATGATGGCATTTGTATTATGCAAACTGTATATCACATCATAATATTATATGGAAATG AGAGCTTGTTTCCGCTTCTGTAGCCTAGTCTACCATTGACATAGCTTCCTGCAGAAGTTACCAGATAA TAGATTGGGAGAGAAAGTCCACACTTCCTTGTGACGGGTTTGTGAGTCCAGCATTTAGGGAAGCCATT GATGTGCTCAGTAGTCTCCAGAGTTCTCTAAATAAATGTGTCCTTTTCAGAAAGGACTACTGATTTGA TGCCCCCTCACAGAGATCGTCTTTAAATATAGGTCAAAAACTAATGTAGAGGGCCAGGTGCAATGTTT CACGCCTGCACTCCCAGCGCTTTGGGAGGCTGAGGCAGGTGGATCACTTGAGGTCAGGAGTTTGAGAC CAGCCTGGTCAACATGGCCAAACCCCATCTCTACTGAAAATAAAAAAATTAGCTGGTGTGGTGGCCCA TGCCTATAATCCCAGCTACTAGGGAGGCTGAGGCAGGAGAATCACTTGAATCCTGGACCAGAGGTTCC ATTGAGCTGAGATCACACCATTGCACTCCAGACTGAGTGACAGAGTGAGACTCCATCTCAGAAAAAAA AAAATTTAGGGGGAAAAATCAAAAGCCATTTCTGAGACACAAAAATACAGGATTTATAAATTATATAT GGTATATATAAAAATATTTTTAAAATAGTATATATAGCATATTATATATAATGATATGTAATGTTCAT ATATTACATATTTATAAAAAAATCTAATCTCCCTTCTCTTGCTTGCTGAATAGGGGGATGCTTTGCCT GCCTCTTCCTCTTATATTAAAAAATAATTCTTAAAGACATTGTCAGTTCTTGGCTTTTATAGCCTCAA TCACCAAATTGTCGGTAAAATGGCCCTAAATAATCATTAAACAAATGTGTGTGAGAGGGGAAATAAGA AGGATAAGTAAGTATGGGGAGGATTTTGTTATAATTTCAGGAAATCAATATCAATTTTATGTAAAGTT TTAAATAAAGCAATCCCAACTTTAATGTTTGATGTGTGAAAAATTAGGCAAAATTCCAAAAGGGCTTT ATAAACTGAAAAAAACTTTACTAACACCTATCCATTTTTATTATTTTAACCAACTTCTATTGAGCTGC CACTAAGTACCTGGGAAACATAAAGTTGTACAACATAGAATGTGCAGGTAAAAGAGGTTGAAGGAAGA AAATAATAACACTATGATAGAGATAAATTTTAGGATAATAGCTAACACATATGATATGCCAGTCATTG ATCTAAGTACTTCACGTGAATTCTTTAATGCTTACAACATTACTGTGAGGTAGATAGAGAGGCACAGT AAGGATAATAACCTGCCTGAGATCGAGGAAGAAAGACAATGATGAGATGTGAACTCAGGCAGTTTGGT TCCAGAGTCCTCTCCCTTAAACCTCATAGTTTTCAACTTCTCTGATATTGTGTGGGTGATGCTGTTGG GGCTTTCTTCAGGGAAAACTAAGCCAGGAGAGAGAATGGATGCTAGTGAGATATTCCTGAAGAAGGAA AAACTTAAGCCAGGCATTAAAGAATGAGTTGGAATTACCTAGCTAGATAAAACGAGAAGGGCAATCCA GGCAGAGGGAACAGACTGTGCTTTTCACTGAGGTGGAAAAAAAACAGAGTATATCAGAGGAATTGTGA TTCCATATGGCTGAAGTTAAGGGTATATGATGAGGAAGAAATTGATGAGGTTGAATAGAGAGGACTGG GGCTAAATAATGGGAATCCTTTGTTGCCAGACTGAGGAATTTTGATGATGGCCTACAGGCAGTGGCAA CTCTGAAAGGATTGTAAACAGGAAAATAAAATCATCACATATAGTTTAGTTGCCTATCAATTAGAGCT CTCTGGATGCAAGCAACAGAAATCATTCTCTGATTAAATCAGGCAGAAAGTAAATGTGCTGTAATTAG CACAAAGGCATTGGAACAAAACTTACAAAAGGAAAAAGAATCTGAGCATGCCTTTCTGGGCATGTGGC TAGCAAGAAGTATTCCAGTCTGTTTGTGATACTCTCTTTTCTCCATCCTGTGTGTAACTCTGTTCAAA TTTTAAAGTCTTAAAAGAGAGTCCAGTTCACCTTGTTTGGGTCACATGTTAATACATGAGCTAGAAGG GAGCAGAAAACTTTGATTTAAATCCCTCTCCTCCCAAAGTCTCAAAATTAGGGAAAGGCAATTCTCCT GAATAGAAACTGGGTTCTATTGACAATAGAAGAAGGAAATGATTCTGACCAACCACTAAACAATAATT GTCCACTGAACTCAGTCAAGAACATGTAGAATAAGTTGGAGGATAGAGCAAATAAAGGAGATTTGTAG GAGGTAATTATTATGATCTAAAGCAAGCTTGTTCAACTCATGGCCTGTGAGCCACATGCGTCCCAGGA TGGCTTTGAATGTGGCCCAACACAAATTTGTAAACTTTCTTAAAACATGAGATACTTTTTGTGACTTT TTTTTGCTCATCAGCTATCATTAGTGTTAGTGTATTTTATGTGTGGCCCAGGACAATTCTTCTTCCAG TGTGGCCCAGGGAAGCCAAAAGATTGGATACAGCTGATCTAAAGCAACAGGTTCATCTACTCAACTTC ACAACGTGTAGACCTGAAATAAAGACCATTCATATACCAATACCYGAAATATAAATTTGTTTGACCAT GACACGTACAGTAATTGGTTCTCAATAAATGTGGATAGCTTGATGGATAATGTGAATGCAATGTGATA AGGAAACTTCATATTCAACAAAGACTGGAATGTGAGGATTATAATTCCAAAGCACCAGAAGATAGATA AGATAATGCAATGAGACATTTTATGACTCAAGGCAAAGTTAGTTATGAGATTCAGACCAAACCTTAGA CGTGCAGTAATTGAAATATTTGCCACAGAAGGGGTATAAGGACATGACATTCAAGTAAGCTAACCTTT CACTAGCTTTAGACTTTGAACTCAGAAAACATATTTGGTGAAAAGCTTATGGTCCCCTTTAGTATGTA TTGCTTGATTAAAGTATTATTTTAGAAAATGGTGAGCTGCTTCCATTTTGAAATAAAAATAATTTTTA CTAAGTGAATTATATTCAGTGAAAAAAATGGAAGCTACAATTACAACTTTAATTTTTTTAAGTTTTAA GAATACAGCCATTTAAAAAAATTAAGCAAATCTGCTTCATTTTAGACAGTAGAAAATATACCATTATC TTTTAGAAGAATAGAGATGTGAAATATGCAAATTAAGCCTTTAGAAGTAAAGCACACATGAAGTTCAA AGTTTAATTTCTAGAATTGTGAATCAATAGCAGTGGATGATTTGTACTTTATAGCTTAGTGTCGGAGA AATCTGATTAAAAAATGCTTTTTCTGTTTCATCACATAAACATAAGTAAAATTGCTCTGAAACAACAA TATTTGACAAGAATTAGCAGTTTTCTTTTTTGACATAATCTATCAAATGAAGGGAAAAATATGTCCTG GGTTTTGCTTTGAGAGTGATTACTAAATCTGACCCTTAAGGAAAGGAAGGAGAGAACAAAGAAGGGAG GAAAGAAAGGGAAGGAAGGAGGAGGAAAGGGAAAAAAAGAAGGAAGAGAGGAAGGAAAGCAGGAAAAA GGGGAAGGAGAGAGAAAAGACAAAAGAAAGGTAGCAAGGAAAGAAAAAAAGACAAGAAAGGAATATTA AAGAGGACAAAAGAGGAGTGAGGAAAGGAGGAAATGGAAGAGGGATGGTGGGAGACAGGAGGGAGAAA GGTGGAGGGGGAAATATGAAGAGAGGTTCCCAGCAGTGGAGACTAGTGTTGCTATCAACAAATAGAAT TTAGATGGCCATATGATATTATTTTTCATAATACTGGTGTCTGATTGCCTGTGCTGAGTTAATTGTAG TCTTTTTTTTCAATTCCGTTTGGCCAGGTGTTCAGGATAATTCACCACAAAATCTCAACCACTGCACT TGTATTGAATAAAGAATTGAGTTGGCAAAGGCATTTTATCCTCCAGTAAGACCTTTCCAGATTGGGGT TGAGACAAATTGGCCAATCTGGACAAGATGATAATAGCATTGTTCAAGATTAATTTTTAACCACACAT TGCACTGTTACCTGGGAGATTTCATTATCTAAAAATTGAATGAGCAGTTTTAGTGGGTATAGTGTATA TTTAAATGGGACATAATTACTTGAATGAGTTTAATTTTTGTTGTTGTTGTTAAGGTCAAAGTACTTAA AAATTATGATTTTTTAAAACTCTGTCTATACACAAAAAGCATTTGAATTAGCTACAGAATAATTCTGA TTATAACTTTTGGTGAATAGATTCAGTCAAAATCTGATTACTAAACAACTTGTGTAGTATAGCCCTGG AAGAATTGATGGGACAATGTGTGGGTAAAGTGGCATTGGCTATTTAAACTAAAAGCAATACAAAACAG AATGTTTCTTGGTTTTATTCTGTTGTCACAAACCCAGCAGAAAGTGGCTATTACAATAGTTTCCCTTA TTCAACAAATGAGAGAAGTTATAGACAATTTAGTTAATTGATCTAAAGTCACTTAGTAAATGTAATTG TCCTAACATAAACCCAGACCCCCAGACCTCTTGGGAATAGATAATGTTTCTTACTTCTTTTCTATTTC CTCAGCCACCCCCCTCAACTTCTTACACATCTCATTTCTCCATCCAAATTATAACAAAACAAAGCAAA CATGGTTTATTTCCATGGGCATCAAATGGATTTCACGAGGTTGGGTGACAGTCATCTTAGGGTGAGGA GATTGATTATTCTGTTTTTCTCTTTCATCGATCAACAATCCAGCCCTTCTCATCTCATCATTTCATTT CTGCACAAACTTGTTTAAGAAATACCAATTAAGAAATTAATTAAGAAATTAATGTTGTAATCTGTTTG GCTGAAGATATTTACAAATTTTGTGCTTTAATTATCTTCCAACAAATGTACATGTCTCTGGTAGACAG CTTGCGACCATCTGGATGACTGATCCATATTTATATAATTTTCTTTCTTTACCTAATGAGACCAAATC CACTATTATCTTCAACGAAGGATGTAAAGATATGTCAGTGTCAGTAATGTGACTTATTTTATATTCTC TGGTCATAACAAAAATAAACCGCCCCTTAAATAAAAAGGTCATAGAGTTGCAAACACACACACACACA CACACACACACACAAAATCATATTTTCTAAGTCTCCTAATTACCTTTTTATGGAAAATGATACCATAT GCTTTTTTCTTAAAGAAACTACATAAACTTATAAACTATACTAAACTACACATTTCAAAGTCTATGAA TGGAAATGTGTATCTTATTATATTTTAATTCAATTCACTGTAAACTTTTCTGTCAAAATCTTATCAAG CAAAACTGATCCAGGATATTTACATGAATTCTGATGGAAGTCACTGTACTGTGTTTTCCATAAAATAC CAGTGGGATTCTGATAAGGAAGTTTATGTTTGCCATTGTGTTTAAATAGAGAATTCTGGGCCGGGCAT GGTAGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGTGTATCACCTGAGGTCAGGAGT TTGAGACCAGCCTGACCAACATGGAGAAACCCCGTCTCTACTAAAAATACAAAATTAGCCGGGCGTGG TGGCGCATGCCTGTAGCCCCAGCTACTCCTGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCA GATGTTGCAGTGAGCCGAGATCACACCATTGCACTCCAGCCTGGGCAACAAGAGCGAAACTCCGTCTC AAATAAATAAATAATTAGAGAATTCTATTTACAAATTTCCTTTCTTGGATCTAGTTAGGGCTCCTTTA TATGGAGTGATTTTTATTGTTTTCATAGAAATACGTAGAATCTGGGTCTTCTCTAACTTTCTTACAGG AAAGCAATGTAATAAGGTTTTTTTTTAATTTTCTGAAAGTTATATAATGTTATTGTTCCCTAAAGTTT AGGACCTGCCTTTTAGGCTTTCCATTTCACCATAACTTTTGGTCCTTAAAGTCTGTAATTGAAGTTAC AGTGTGTTATGATGTAAATTTTTCTTATTATTACCTTTAATGTTAGGGTAATGTTAACTAATGTTAAT GTTAGGTATATGGTTGTTTTTTTCATTCCTTCGTTCAACAAATTGTCTTTGAAACCCATGTTACAAAG CACTCTAGAGTCAGGTTGAAGACTATTAAGAAAGGAGAATAGAAAGAGACACTAGAGTAATAATTTGG ATTTAAATTTGATTTCCTTGTGTATGATAGTGAATAAGTGTGAATAAGATGAGGCAGTGATCACACAT CACTATTAGTAAAAGTGTTTCTGTACCTGTATCCACACTTTTATGTATATGGTTACTTATGTTAAAGT GATACATATTATATAAAATTAACGTATACATTAAGTAGATATTTTAATAGTCTGTAATTAAATACTAC TAGTATTTTCTTTCCTCCTTCAAGTGCTTACTTTTGATACCTCGAGTTACAGTGTCATAAAGATTCTT TAGAAATATATTGACTGTCTTTTAAGAGCTTTTGATACAATACTGAGTTTACATTCATCTGTTATTTA TTGAACACTTGCTGGTGAAAGGCATCAGTGTTATCTGCTCTTAGGGAACAAAAATTAAAAAGGGATAG GCCCTAATTTTAGAGTGTATCCTCTATAAGAAAAACATAAAAGATAGGGCAGTCATGGCCACAAAAGA AAAAAGTGTTATGGTGGTTTCAATCATATATGTATTAGAATGAATAAATCAACTGATCAATTGTGATT TCTTATTCTAAATATGTGCCTGCCTTTTTCATATAGATGAAAATTAAGCTATGTTTATCTTTCCAGGG ATCTTGTTGATTTTTATTCAATAACTTGGGAGTGAAAGTTGATTTTTGCATATGTTTTAATGTTTTTA AATTTCATAAATGAATTGATCAGTAATTTCCAAGGTAGTAATGGCTGCATTGTTTTTGAAAAAAAAAA AGCAACAGGATTTGA7TGTGCTTTTATGATTTTTAAAGAATTCATTAAAAATAATGCCACGGTTTCTA AAATGATTTGAGTCAATTTCTTATTCGATTTATAAAAATAACTTTGAATACAATTTTAGTAATTCACA AATGCTTTCAGTTCCCTTACCTTTATATTTTATATTCTGTGTAAACAAGTGACATAATATTTAAGAAT TATATATCTCCTATGATTTATTCAAGAAAAGAATATATACTGTATTATTTATTTCAAGAACAGAAATG CTTTGATTTAACTGTCATCTTCTCTCTTCAATTATGGAAGCAAAATAAACTGTAATGACCAATGTAAC CCCTCCCCCATATCAAGTTAATCTATGTTCAACTCCAGAATTATTTTTGAACACTCAAACTAGAAATT AAAAAAAATTAAATCCATGAAGACGATTTTTGCCAAAAGCATATAGATAAATTGAGTTGATTCTATAC TTAAGAAAGTGGAGAGGAGAGAGTAATTTGGAGAGAGTAATTTACTCTTAATCCCATATTTTTTCCCT AAATGTGAAAGAAGTAGATTGTAGTGAGAGGGAAAATAACCTGTAGCAACTTCATTGAGGCTAAGCTT TCTGTCATGTTATATTATACGAAAGTAATGAAATGCTTCCACAGATAGAATCAGAAGTCCCCTCTGAG AAATTCTACATAAAAATTAGCCTGCCACTTTACCACACTTACTCAAGTTTGATTTTTTTAAGTTATGT AATAGATGTTAGGCACTAGAAGAGGACATTTACTGGGGGCAAAGATCAGTAGTTGGAAAGAATGCAAG CAGGCAAGAAGCTATATATAATGAGATTTTACAGTACAATTGTTTTCTAAATGAAAATGAGGACGGGT CCAGACACAATGGCTCACACTTGTAATATCAGTGCCAGGATGGAGGATCCCTTGAGGCCAGAAGTTCA AGAGCAACCTGGGCAACAGAGTGAGACTTCATCTCTACAAAAAAATGAAATAAAAAGTTAGCTGGCTG TGATGGTGTGGGCTTGTAGCCTTAGCTACTCAGGAGGCTGAGGTGACATGATCTCTTGGGCCCAGGAG TTCGAGGCTGCAGTGAGCTATGATAGCGCCACTGGATTCCAACCTGGGCAATGGAACAAAACTCCATT TCTAAAAAAGAATAAAATATAAAACTAAAATAATAAATAAATAAAAATGAGGATATATTTTATTTTAA CATTTGGAAACTTTGTAGGTGAGGACCATGCAAACATTCAAGGTGTGAGTTCTGACCAAATCCAATTA TTAACCATACCAATGACTTAAGGTTTCTTCACACTCCTTAAAGTTGATTAATATAATGATTATATAGT TGACTGGTATGTCACAGCTTGAAGCCTTTGAGATTTATTCCTGCCTTTTCTGTAAAGGTTGTTTTGTT AATTCCAGTATGTACTGGTCGTTTTTGTTTTGTTTTGTTTTTGTTTTTGTTTTGTTTTTTTGAGATGG AGTCTCGCACTGTTGCCCGGGCTGGAGTGCAGTGGCACGATCTCGGCTCACTGCAACCTCCGCCACCT AGGTTCAAGCGATTCTCCTGCTTCAGCCTCCTGAGTAGCTGGGATTACAGGCACTCACCACCACACCC GGCTAATTTTTTTTATTTTTAGTAGAGATGGGGTTTCACTATGGTGGCCAGGCTGGTCTCAAATACCT GACCTCATGATCCACCTGCCTTGGCCTCCCAAAGTGCGGGGATTACAGGCGTGAGCCACCGTGCCCGG CTGCCAATATGTATTGGTCTTTTTCATCAATGATTCAGTCCAAAATCATTTTGTCCTTTAACTATATA TTTTCTTGTAAAGCTGCTTCTGTTGTCTTGAACTTTTCTTTTCAAATGTATGTTGTCATTTGACTTTT TAGATTGTTATTTTCTGGTCCTCGAAATAAATTTAAATTTCCTGTAAAGGAAGGTGTAATATTCTATT TGACATAGCCGCTAAAGATGTACTAGGTGCTTTATAAATATTGTTGATTTACTTTATCTTCACAGATT ACTAGTTTTACTTAGTATTTGGAATATGACAACATTTTATAGAGCTATATTCATATATATGTTTATCT TAACTGTTAAATGCAATATGATTCATGTCTTGTTTTGGTCAATGATGAATGAAAGTCTCCTGAGAATT AAATTTACTGCATCGATGCAAAAACAATCATAATTTTAGACACTCTAAGAATTTTAGAAATTAAAGGA TTTTTTTTTTCCAGTTTACTCTGTTAAGATTGTGTTTAGCTATGCGTGACAGCATTCTCACTACAGTG GCTTATCCAGATAGTTTCTTTTTCTCATAGAGCAAGACTTCCAGAATTATGTGTTCCAGGGTCAGTGC AGCACCTCCAAAACCGTATGTCCCAACTTTTTCCTCCAACCCCAGTCATCTCCAACATGAGACTTTCT TTTTGTTTTGTTTTGTTGTTTTTGTTTTTGTTTTTGTTTTGAGATGGAGTCTCTGTCGCCAGGCTGGA GTGCAGTGGCGCGATCTCGACTCACTGCAACCTCTGACTCCCTGGTTCAAGGGATTCTCCTGCCTCAG CCTCCTGAGTAGCTGGGATTACGGGAACGCACCACCACGCCCAGCTAATTTTTGTATTTTTAGTAGAG ACGGGGTTTCACCATGTTGGCCAGGATGGTCTCGATCTCCTGACCTCATGATCTGCCTGCCTCAGCCT CCCAAAGTGGTGGGATTACAGGCGTGAGCCACCGTGCCCAGCAAGACTTTTTTTCCTGTGGTCTCAAC ATGGCTACTCTGCCTCCAGGCACTATGTCTGTACTTTAAAATGGAAGAAGGGAAAATGGGGAAAGTAA AAGCATATTCCAGCTGTGTCAGCTCCTGTTTGTAAGGAAAACCAGTGCTTTTCTGGCAGCCCCACACA GAAGAGTTTCTACTTGAACAGTGCATTAACCAGAAATGTGTCACGTGACCATTCCTAACTTCTAAGGA TCTTGGGAGGATTGAGTGTTTTAACTGAATAGGTGTGTTTCTTTCTTCATAATTCAAAATGTGAAAAT TGGTAACTTAGTTATAAAACCTTGCTAGTCTGAACAGAATTTGGATTTTTTTAGCTAAGAAGGAAAGA AAGGGTATCGGATAGGCAGCTGGCTATGCTAGCCAAGATACTCTTAATAATGCACATTTTTCTTCTTT GGACATAAGCAGTTTTAACTTAGCTAAATATGATGTGATTGTTTTCCTGTCTTCTTAGTTCTGTTTAA ATTTGTTTCAGAAATCAAGGAAATAAAATGGAGAAAAAACTCTATTATTCATGTCTATCTTTCTGCCT CTGAATATTTTTATGTTGGAGAAAGAGAAAGCAGTAACTTTCATAATAGCTTACATAGTCTGACAAAT TCTAAACATGTCCGTTAGCATCAATATACGTGGTATTAGGTCATCAGTTTTTATATTCTGAATTATTA AGACCCAAATAAACCCACTGAGTTCAAGAGAAAGTATACACTGAGCAATAAAAACATTACCAGTTCTA GCAATGATAATCAAACAAGAAAACAAGTAATATAGTCTGTTTAGAATAACATGTTTTAAAGATCAAGT TTTTCTTCCTTACCAATGTTGCCTTTCTTGTAACACTTTTTTTTCCTTCTTGAGATAGGCTTTCCTAT CTTTTGTCACAAACCCCAATATTTACATGGCCATTCGTAGTCTATTCATAGCAGCACCACCCCATGGC CCAAACTTGTAGATATTGCCCTCCTTCTATGGTTGTTCTAATAAGAATAACCACTCTTGTCTCTCATA ATCTCAGCTGTTTTGTGCCGTTAAAATGGAAAATAATGAGTATTAAGATACTAACTAGGGGCCAGGCG CGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGATGAGGCGGGCGGATCACGAGGTCAGAAGAT TGAGACCATCCTGGCTAACACGGTGAAACCACGTCTCTACTAAAAATACAAAAAATTAGCCAGGCGTG GTGGTGGGTGCCTGTGGTCCCAGCTACTCGGGAGGCTACTGCACTCCAGCCTGGGCGACAGAGCAAGA CTCCATCTCAAAAAAAAAAAAAAAAAAAATACTAACTAGGTTTCAGTCATATGAGATGAATAAGTCCT ACAAATCTGTACAGCCTAGGGCTTGTAGTTAACAATGTTTTATATTTAAAACTTTGCTAAGAGAGTAA ATCTTTTTTTACCTGTTATTATCGTACATGCAAAAATAATAGTAAATAAGGAAGGTAAGAGAAAAATT TTGGAGGTGATGCATAGGTTTATGGCATAGATTCTGGACATGATTTCACAGGGGTATACAGTCATGCA TTGCTCAACAACAGATATACATTCGGAGAAATGCATGGTTAGCTGATTGATCTTGTTGTGCAAACATC ATACAGTGTACTTACACAAACCTAGATGGTACATCCTACTATACATCTAGGTTGTATGGTATAGCCTA TTGCTCCTAGGCTATAAACCAGTACAGCATGTGACTGTACTGAATACTTCAGGCAATTGGAACACGAT GGCAAGTATTTGTGTATCTAATCACATCTAAACATAGAAAAGTTACAGAAAAATATTATAATCTTATA GGACCACTGTCCTACATGTATACAGACTGTGCACATGATAGTGGTCCATTGATCAAAATGTCCTTATG CAGCACATAACTGTAATTATCTCGAAACTCATCAAGCTGTGTTCATTAAATGTGTATAGCTTTTTATG TCAATAAAGTGGTTAAGAAATCAATAAAGTGGTTAAAAAATATTTTGACTAGGAAATATACTATCATT TCTAGTTGATAAAAGATCTCAACATTTCCAAAATTGTCCTACAGAAAACCAGGTTCATCAGGTGTTCA TACATGATCCTCATGAAAAGGTCAAATAAGCTGAAAAACATGCATAGACGTTGCCTATCCTAGCAATC TATGATGTACATCTCCATAGTAAGGTCACTGAAAAGTCTTTTAGGAATGTTAGTATTGTTAGCTCAGT ATTTCTCAGTGATTTCTCCATGGAAACCATTTGTGTAGAGCATCTTGAGGAGCACAGCTGAGAGAACA TTATCTTAGTTGGATGTGTATGTCCCTCTGAGTCACTTGATTTCTCTACATATGCTTTTACCAAATTA ATCTTTTAGAAATCTT7TCTCTTCGCACTATGTCTATAATTTGTGAAGTTGTTACCAGGATAACATTT GTGCCTCTCACCATGATGTACCTACCAGGGTCCAAGCAGCCATTCCTTCTCTAGAGCAACTGTCTGAG GGAAAGAATTTAACACAGCATTCTACGAAATCATTTTATTTATAAAAATAGATTACTGCTTTACATAT AGTAATTTATATTTAGAATATTGATTAATTATTAAAATCTGCATGAGAGCTTTAAAGAGTAGTACATA ATATATAGCAGTTTGTACTCAAACTGTCTTCTAAAAAGGATTCACTTTTTGTTTGTATTCTATTGTCC TATTCGTTGATAGTGTTACGTAAGTAATTATAAAACTTAAAATCTGGAAAGAGAATGTGGACTCAGAA TGCCATCTCTTTTGTTATTTCAAATGGATTAGAAATGAACATACATATTCATTTTCTTTCATTACACA TCCAGAGAAATAGAATGGATTTTATAAATATGTAAAAGCAAGGATTTTGATCACTGATAAAAAGGGAA GGTTTGGTCACTACCTTATTTCATTCCTTTTTTCTTATCCTTTTTTTTTTTTTTGTCAATTATTTGAT GACATCTCTGAACATCACCTTTTATTCATGACAAGAATTGGGTATCATGGTAAAGAACACTGTTAATA TAATTCAGTTACTTCACCCCCTCCTGAAATATAGAGAAGCTTTAAGACTATGTGAATATTTTTTTCTG GTTTTCTTGTATTTGTAGAAATAGCATGAGCTTTGTTTAAAGTCAGGCATCTAAAACCTTGCCCTGTA TGTTATTGACAACCTGCACAAATTTTAGGATCTATTCTATTACAGTTTGTTCAACTGTAAAACTAGGA TAGCAAACTCTATGTCATATTTTCGTTATCAGAATTTAAAAAGCATGTTTTAAGATCTTAGTAAATAA TAAATCTCTACTCTGTAGTTGAATTTGTTCTATATTCTTTAAGAAATTCCCTTTGATGGTTATGCCAA CCTCTGTATTACTTTTCTTCACACTTTAACTTTGCGCTGAAATCATAGTAGTATTTTACGTTATCAGT CAAAATAACAGTCATCCTTAAAACAAATATGAATTTTAGATGATTAAATAGATTTGTATGGAGGTTCT TCTTGCTAATCATAGCAGTTATCCTTGGTGAAAAATGATAGACACTTGAAAAAACCAATTAATCATGA TGGCTATTTTTGCATCATAAATAAAGCTTTCAAATTTGAGAGGGAATCAAAAGGGCAATGGTAGTATA GTGTCTCAAAGCCCCTTTCCAATTGATGGTACAAATTTAAAAAGAGAGAGAGAGAGAGAAACATGTTT CACTGTAATTGTTTTCTAAGAGCTTCCAAAAAAGCGTATTTTCTTAATAGATTCAAATTTTTCAGTTG GATTGAAAGGGAAGTCTTGGAGTGTAGTGAGGAGGGCACCTTCTGTTGAGAGGTGTTCAGACGACAGA GTGTGCCCAAGGCCAAAGATGAGATGGTTTTGCGAAAGTCAGTGGCCACAAACAGGTGTGTTTGACCC CTGAGAGATATGCAGGAAGTCTACCCCACTTTAATTCTTCCAAATATTCTTTACCTTAATTCCCAAGT ACTTGATAAAGGAGCAATGGGGAGAAAATATGCACACTATTATGGAAAAGTTTTGACCTACACTTTGG AGAGTTTTAGATTAAGAGCATTCTAGAAATCAGTCCCAAATGCCTAGGGTTTACTTACTTAAAGATAA TATCATAGTTTGGGTGACTGGGAAGCATACCCTGAGATTGAGGTGAGCATGCAGTATGTCTATTTAGG AGTGTTCTTGGGGTCAACGTGTAGGGGCAGAGGGAGAAGTTGAGCTCTGACGCAGTCTTAGTAAGGGC CTCAGCTGACCGTTCAGGGAGTTCTTAAGCTGGAATGACCCTTCAGAAGTGCTAGGAAACGAAGAAAG GGGACTGGATCTTTATAACCCCGTGTCAAGTCATGCACTGGATGTGGGCTACTCCAGGAAGGCAACGA ACTTTAGCAAGATGATTCTCTTTAGCCACGGGAATTTCCATAAGGGGGCTGCTATGGTCTGAATGTTT TTGTCCCTCCAAAATGTGTATGTTGAAACCTAACACTCAAGGTGATGGTATTAGAAGGTGGGGGTTTG GGGGGGTGATTAGGTCATGCGGGCTCTGCCTTCAGAAACAGGATCAGTGCCCTTATAAAAGCGGCTCC AGAAAGCTTCCTTGCCCTCCCACCATGTAAGGACACACCGAAGATGCCATTTAACAGGAGTGGGCCCT CACCAGACAATGAATCTGCTGATGTCTTGATCTTGGAATTCCCAGCCTCCAGAACTATAAGCAATAAA TTCTGTTGTTTATAAATTACCCAGTCTAAGGTATTTAGCTATAGCGGCCCAGACTAAGACAAGGGCTG ACAGCTGAAGGCTGTCTACCAGCAGCACTCCTAGCAGCTGGGGAACTAAGTCCTTCATTTCCAAAGGG GAATCTAGGCAGCATATTTACAGCTTTTCACTACAGATAAGCTCATTATTTCAAATAGGGACTAGCAG GAAAAAATTAAATTGCCCAAAATTTAGTGGGATGCTGAAATAGATTGTGGTGTGTAAATTGGAGTATA GTGAGGAGAGCACCTTCAAACCAGTATGTACTACATGATATTGTTTTTGTTGCAATATTTATTATATA CCCAAACACACATATATTACTTTTAGAAACACACACCACATATATATCTATGAATATTTTATATACAC ATAGGGAAGGATTGTTGATGTTATTTATGCTATTTTAAAGATCGATGTTTTCATATAATTATGTATTG GTTATATATTATTTCTTGATATAAGGTAAAAAAAAAAAGCAAAACAAACTTTAAGTGATCACTATGAA AAGAATCCCAATGCTGCACATTTAGGTTTATCCAACTCTTCCCATTAAAATATTAAATAGTAGAAATA ATTGTGAATAAGAAAGAGCAGATTTTGAAAAATGGAAAGAAATGCTTAAAGACATAGCATTGTTGCCC AACCATCATTATTTAAACATACAGTGTTTGGCTTTGACCAAATTGCCTTCAAACACTTCCTTTTGGCC CAAAATGTTAGGTCATATATACTACCATAAAATTCATGATGCTTACCATGCATTAATTTCTAGTATAT ACCAGGCATTGTGCTATGCATATCATATTCAATATTTCTAATCCTCTCAAAAGTGGTACAAGCTAACT GGCGTTTTTCTTGTTTTGAAAGGGAGAAACTCAGAGAGGTTAAGTGACTTGCCCAAGGCAATGCCATT GATAAGTGCCAGATTCTATCACAGGTTTATTGGCAACAAACCATATGTGCGCGTGCATGCGCGTGTGT GTGTGTGTGTGTGTGTGTGTACACATACACGAATAACATATATGGTATAAATACGTGGAAACATAATA AACTGCATTGAGCTGCGTTTATAATTAGTATTTAGGACATGTTTGGCAAATAAAAACAGTGGAGATTG AAATGGATTTGCTTAGGAAAAATGATACATTAAAATAGGCTTTATTATGAGTCTTCAACTATTCTGTG AAAATAGATACCCAGGGAAGAAATAATAGAGAATATGAATCTTGAGCAGGCAACTGAGAACTTGTCGA AGAGCCAAGATAAAAATGTCAGAGAGGAGAATATTTTGGCAGCTCAGATGAGCCCCCAGAGGGTGGGA GGCAATGATCTCACCGCAGTCTCGTATCTGAACCCCAGGTTTTTGCATCTCCATAAAGTAATTTCTTA CACCCCTCAATAATGATCGGGCTTACTCTCAATCTCTCGCTCTCTCTCTGTGTCTCTCTCACGCACAC AAACATGCAGAACATTTCTTGCACATGCATAACTCATAAGACGATTATGTAAATACCAGCCTTTTTAT TTCATAACTAAATTACAAGGCCTGGTTATTGTTTGGACTGTGAAAAAATAATTATGTGAATAGGTGCC TCAAGATGAAAGACAAGGCAAGATTGTGAAATTATTCATATGATAGTAATAGTATGCAAAAAATAACA CAATCTTTAAAGATCTTTAACGACCTAGTTATAAAACCATGCTTTATAACAAATATAACCATGAGGAA ATAAAAAGAAAAATGTAATAATATACTCCAAGAATAAAGTCAAATGTATTGTTGAATGTAAGGAGTTG GTTACACTTCCTTATAGTGGAGGTTATTTTAAAATTTGTGGCTTACGTGGTGTTATGAATTGCCCTAG ATCAACACTATTATGCAAGGCCAACTATTAGGTTATTTTTGGTAGATAACCACAGCAAAACTTTAGTA TAATAGGTAAAGGTTAGCTACACTCCCATACCCTCACTCTCAGGTGTTGTCATACTCCGTATAAAAGG TTCAATCAAGGGAGACATGAGAATATTCCAGAATCTAGAGGCAGGATGCAGTTAACCTTAGAGAAGGC ATCAGACAACTAGAATCTTCGGATTCAATGTGGAAACAAAGCATAGTTTAGGCATTAAATCTTGGGCA CCATTCCAAAGAATACAGGTTCCATAACTTACTATATTTTTATACCTAGCAAGCTAGAGATGAGGAAT TGCTCTCAAATATTTTAACCAAAGCATGTATCTTAAGTAACACTAATCTCATAAGTGAAAACTCATTT CTAATATTCATTTTGCTCATTAGCAAGGCCTCTAGTGTTGACTGTGATAAAAAATAGTTCAAATGCTG GTAGAACCCACCCCAGGAGACTGGCCTTTCTGATTAAATTCTAACTCTATCCCCACGTGAATTCCTGA CTTAAGTAACTGAGTTCCTGCACATCAGAATATAAGTATATTATAGATATAAAAACATATGTAATTAA TAAATATTTTAAGTGAGACACTTCTTTCATCTTTATGGCTTAACTATATCAGACATTTGATTATTTTT AGCGGTCTAACTACAAAACAAAACACAAAGCCCACAACTAAAAATTTCTTTGTATATATTGCAAAGAG GCAACCATTTGGTGTCAATTCAATCATGAGTGAAATGCTATTATACGAGTACATCTCCCTGGCTTGTA TGGGGGTAATAGGGCATGGAATTTACAGATTCACAATAACTGAGATATTCACAATAACAAAGATATCA ATATGTAGCTTTTCCCATAACTTTGTGTAATGAAATCCTCAGTTTGTGCTGTGTAAAAAGCTTATTGT TTACTTCTCATGAAAATCATCTTAGTTTTTATCTTTATTTAATAGTCTGTAATTTGGGGGTAATACAT TCGTTTTGTTGATACTATGTGAAGTGGCAAGCAGAAAATTCTAACAGGAATAGATAAGCAAGTATCCT ATAAATCAGAGTCAGTGTCTCTCTCTCTCTCTTTTAATGAGTCAGTCTGTCTCTCTCTCTTTTTCCCT GCCTGGCTATCTATCTGTATTTTTCAGTTTTGCTTTGCAAATAAGAGAATTGTGTGTTGTAAACCAAC CAACTTACCATTAATTTTCTCTGAATTCAAAAGCAATTACAAGCGGACTCTTGAGTTTGTGCTGCCTG GTTGTCTGCATATAGGCCAGATGTCTAGAATAGGATCTTTATTTACTATTTTTACCCTCCTAATTTCA TGGTAACTCCAAGGTAGATGATATTTGTAATCGTACACTACTTGTCAGAAATCTTTCTAATAACACTG CTATTTTATAAAAATAAACATTAATTCAGTATAAAATTTTATTTTAAATTGTTAATTCAAGCAAATCA GTGAGGTAACTTTTACACTGCCGAGCGTACGTGTGTGTGGATTAGTACAGCCATGCCATAGACTTCAC TTGTAATCTTTTCTTTATATTTTTTATACACCTGAAATGTTCATCATTGTGCTGTAGAAAACAATCTC ATTGTGTTTTTAAAAGCTAGAGTGGGTATTGAGAAGGGGAAGAGGATCATAGAAAAAGTTGGTTAACA TGCTACTTAACACTTCAAATCTTTACTCGATGTCATCATCAGCAACATTTTAAATTTATGCTTCTACT AGTTTGCAGTTCTTTTCCTTTGATTATTCTTATGATACAAGCCTTTCCACACAAAATTTATGTACAGG AATTGTGTAGAATTTTTCTTTGGAAAATATGGTGATTTATTACAATTTGGGCAACATCATCATTTTAA AAATTCAGAATTTGATTTTTCTCAGAATCATCAGAAAGAATAAAGCATATATATGGTTCATGTCAGGA GAATTAGAACATGAGAATTAATATATCTCTGATCTTTTAAAATATTTTCATGTTTGTGAATCAGCAGA TTTTTCCTAGTTTGAGATTTAAAAAATCTAGATATAATTAAAATCTCACTGATGTTTCACCATCAGAT GATTTTATATTTGTATTTTCTTCCACTTCATAACTTGTATAGAGAAGAATAGAAGAAAGAAAAAGGGA GGATTGATAATCTTTCTCTCTCAGTTCTTATAGCACTTCATTTTTTAAACTTATTACTTCCTTCTGCC TGCTTTGTTTGTCTACATGTTTGTATTTCATGATTTCTTAGAAATCCATCTACTGCCATTCTGAAGGT CATTTACCTGAAAATGATAGAAAGCAGCATATATTCAAACAACTGCAGAGTAATTGTCTATATCAGTT ATCATTGTTCATTACTTTTCTGTTTTAGGATTGAGGGGCTGCCTCGCCACCTCCCTCACACCCCCAGC ATATTATCACAAAGCCTACTGATTCATTCACATCCCTGGGCTGAATTTGCCACCCACTGTGTGTTCCT GTTGTTTTGTGTATGGAAGTGAAAAGATTTAATTTGATGTTGTTGAAAAGACACAGAGGCTAACTTTC AATTTTCATATGTAGTTCTTCCCTCTCCCTCTGCACCACCTCCTTTACTTGTTGAGAAAATTGCCCTC TCCATGGTAACAATAGAAGAAGCTTTCAGATTTTAGTAGTAGTTGTTGCAGAGAAAAGAATTCAAAAA GTAGATGAAGTTTAAAAATGAAAAAGAGAGAGGAAGACAGCTGGGAAGAAGGCTTAATGTTTATGAGT GGGTGTGGAGGGGAAGAACTAAGTTGAATGAACAAAGCTGAGCTAAGGGGAAGATGGTTTTTCTGCAT CCCAGAAGGCAATACCCTAGCCTTTCCTGCAGCCTTCACTCCCCAAAAGATAAGAGCTTTATCTGAAA TTCTTATAGGATTCATTCCTGAAGAGCAGCTTGTCACCAAACAGAAACACTGTGATTTCCTCAGGGAG TCACAGTTTATTATTATTTTTTTAATGTAACGCTTTTGTGAACTCCAGTTTCCACCTCAATTCAAATG GTCTTTTGGTTACAGGGTGAAAGAGACCCAACAATACACCTTTCCCACTTCCGGAGGCCTTTGGTTAA ACCATGTCTGCCACAAGGACACAGGAGCCTGGTATGACTGGTTGTTTTTTGTTTGCTTTTTTGCCTCC TGTGCTTTCTAGATTGTGAGATACTGTAACTCTTGTCGATGACACATAGTACCGAACCCACCCGAAGA AGTATGTCAGTATGTCACATTGTGACAAACAGCTTCTCATGCTAAGTAAATGCAGAACCATTGTGAAA GGTTTAATAATGCCCACTCCTCCCCCGCCAAAGATGTCCATATCCTAATCCCAGGAACCTGTGAATAT GTTACCTTACATGGCAAAAGGCTTTGTATTAACAGATGTGGTTAAGTTAAAAATCTTGACACGGAGAG ATAGCCTGGGTTACCCCAGTGCGCCCAATGTAATCACAAGAGTCCTCCTAAGAGAGAAGGAGGTGATG ATACAAGCAGAGTAAAAGAGAGATTGGAAGATGCTACACTACTGGCATTGAAGATGAAGGACAGGGCC AAGAGCCAAGAAATGCAGGCAGGCTCTAAAAGCTGGAAAAGGCATGGAAAAGAATCCTCCCCTACATC CCTTAGAGGGAATGCAAGCTCTGCCAACACATTGTTTCTAGCTTGTGAGACCCATTTTTTGGACTTTG GACCTCCAAAATTGTAAGATAATAAATTTGGGTTGTTTTAAGCCATTAAGTCTGTAATCATTTGTTAC AACAGCCACAGGCAGCTAATACAGCCATGAACATTTAGTAATGACTAACTTTGCACAATTTTAATACA AGCTTCTTATTAAGGTTTATTTTTTCTTAATTACAAGGAATAAAAGTGGGGTCTGGGGGCAATGTCAT GGTCCACTCCGTTTTAGCCATATGAATTTGTATTTCCAGCATTAGAACAAAAGGTGACAAATCTGAAT GTATTTGTGTGAAATAATAATAAAGCAGAACAAAAAGGGAAAAGTGTCCAGCTGGAAATGAAGTTAGA GAAAGATGAGGAGAAGCAAGCCAATTGTGTAGTTTTCCCTTCTGCTTTTTAAAATCATGATTTGTTTA ACCCACTGAATTCTATTTTAGAAACAGGACTGCAAGGAAGTGTTGATGGATTTGGTGGCATGAGAACC AGAGTCACAGAGGCAGGAAAGTAAGGAATAAGTGTTAGAATAGGAAGCAGAGTTGCTTGGGAAGAGAC CTTATGACATGTGGACAGGGCTAGACTTAGGAGTCAGAAAGACCTGAGTTCAAATGCTATCCTTTAGT ATAGTTTGAAGTCAGGTAGCGTGATGCCTCCAGCTTTGTTCTTTTGGCTTAGGATTGACTTGGCGATG CGGGCTCTTTTTTGGTTCCATATGAACTTTAAAGTAGTTTTTTCCAATTCTGTGAAGAAAGTCATTGG TAGCTTGATGGGGATGGCATTGAATCTGTAAATTACCTTGGGCAGTATGGCCATTTACACGATATTGA TTCTTCCTACCCATGAGCACGGAATGTTCTTCCATTTGTTTGTGTCCTCTTTTATTTCCTTGAGCAGT GGTTTGTAGTTCTCCTTGAAGAGGTCCTTCACATCGCTTGTAAGTTGGATTCCTAGGTATTTTATTCT CTTTGAAGCAATTGTGAATGGGAGTTCACTCATGATTTGGCTCTCTGTTTGTCTGTCGTTGGTGTATA AGAATGCTTGTGATTTTTGTACATTGATTTTGTATCCTGAGACTTTGCTGAAGTTGCTTATCAGCTTA AGGAGATTTTGGGCTGAGACAATGGGGTTTTCTAGATATACAATCATGTCGTCTGCAAACAGGGACAA TTTGACTTCCTCTTCTCCTAATTGAATACCCTTTATTTCCTTCTCCTGCCTGATTGCCCTGGCCAGAA CTTCCAACACTATGTTGAATAGGAGTGGTGAGAGAGGGCATCCCTGTCTTGTGCCAGTTTTCAAAGGG AATGCTTCTATAGTACAAGGCTACAGTAACCAAAACAGCATGGTACTGGTACCAAAACAGACATATAG ATCAATGGAACAGAACAGAGCCCTCAGAAGTAACGCCGCATATCTACCACTATCTGATCTTTGACAAA CCTGAGAAAAACAAGCAATGGGGAAAGGATTCCCTATTTAATAAATGGTGCTGGGAAAACTGGCTAGC CATATGTAGAAAGCTGAAACTGGATCCCTTCCTTACACCTTATACAAAAATCAATTCAAGATGGATTA AAGACTTAAACGTTAGACCTAAAACCATAAAAACCCTAGAAGAAAACCTAGGCATTACCATTCAGGAC ATAGGCATGGGCAAGGACTTCATGTCTAAAACACCAAAAGCAAGGGCAACAAAAGCCAAAATTGACAA ATGGGATCTAACTAAACTAAAGAGCTTCTGCACAGCAAAAGAAACTACCATCAGAGTGAACAGGCAAC CTACAACATGGGAGAAAATTTTCGCAACCTGCTTATCTGACAAAGAGCTAATATCCAGAATCTACAAT GAACTCCAACAAATTTACAAGAAAAAAACAAACAACCCCATCCAAAAGTGGGCGAAGGACATGAACAG ACACTTCTCAAAAGAAGACATTTATGCAGCCAAAAGACACATGAAAAAATGCTCACCATCACTGGCCA TCAGAGAAATGCAAATCAAAACCACAATGAGATACCATCTCACACCAGTTAGAATGGCAATCATTAAA AAGTCAGGAAACAACAGGTGCTGGAGAGGATGTGGAGAAATAGGAACACTCTTACACTGTTGGTGGGA CTGTAAACTAGTTCAACCATTGTGGAAGTCAGTGTGGCGATTCCTCAGGGATCTAGAACTAGAAATAC CATTTGACCCAGCCATCCCATTACTGGGTATATACCCAAAGGACTATAAATCATGCTGCTATAAAGAC ACATGCACATGTATGTTTATTGAGGCACTATTTACAATAGCAAAGACTTGGAACCAACCCAAATGTCC AACAATGATAGACTGGATTAAGAAAATGTGGCACATATACACCATGGAATACTATGCAGCCATAAAAA AGGATGAGTTCATGTCCTTTGTAGGGACATGGATGAAATTGGAAATCATCATTCTCAGTAAACTATTG CAAGAACAAAAAACCAAACACCGCATATTCTCATTCATAGGTGGGAATTGAACAATGAGAACACATGG ACACAGGAAGGGGAACATCACACTCTGGGGACTGTTGTGGGGTGGGGGGAGGGGGGAGGGATGGCATT GGGAGATATACCTAATGCTAGATGACGGGTTAGTGGGTGCAGCGTGCCAGCATGGCACATGTATACAT ATGTAACTAACCTGCACATTGTGCACATGTACCCTAAAACTTAAAGTATAATAATAATAATAATAATA AAATCTCAAAATAATTAAAAAAAGAAACAAACAAATGCTATCCTGATCCTAACTGGCTGGCTGTCTTT GGGGAAGTTGGTAATCTTTTCTGTGCTTATTTCCTCATGTGTAAAAAAATGAATATAGTACCCAGCTA GGTAGAGTTGTTGTTGGGATTAAATGATGACTATAAAGCATCTAGCCCAGCTTCGGCTACATTATAGC TGCTTACGAAATTGTAGTTACGATGTAAAAGAGAAAAACACTGGAAAAGGAGGATATGGGCCATTTTA TTCCACCTTCACCACCTTTTAGCTTGGTGACCTTGGGCAAATTATGCTTCATTCCGTGCTTCATTTTC CTTGTCTATAAAAGGGTGTAAGTACAGAACCATTGAGGGGTGGTCATTATTAACCTACCTCAAATGGT GTCTGTAAGTTAATATATATTGTGCTTTTCCTATGTACAATATCTAGCACATAATTACAAATCAAATC CATCCCATGTGCAATATCTAGCACATAGGAAAAGCACAATAACTAGTTATTACTCTTGTTGTAGTAAT TGCTACGCTGTAGGAGTTTGAATTGTAAGGCAGTGGAGAGTCACTGACCTTTACGAGAAAGTGTAGCA GAACATTTGAGTAGATAGTAATGGGGAATATTACATAAATGGATAGATATTAGGGGCAGATATTACTA TTAAAATATTACAGCATGGATATTTATTAAGGCCAAACTGGTTAATTAGTTGCATCTCTCAGGTTCCT AATGTTGCTTAATTTTTTAACCTCCCATTTTGTGCTGCCCTTTGTACGAATATTTAATGCTCCCAACA CCTCTTCAGTAGCACATGTACTGTGAGTTTGTTTTGTTATTACTTGTGTGTATTAGCATTCCTTTGTG AACCAAAAGCATGGAATTAGCTGTTGCCTCTAGGCTACCTAGTTTTGTAGTTTGGATTGAAGCCTTCA CCTCAGTAACACCTATTCTGTCTACTATCTTACAGAAAACTTGTAAAATTAAGACAGATCATTAATAT AGCACAAAGAGACAAAGGGCAGAGAACATTGAGATACTGGATATTGGAACCACCCAATAGTGTTGATT TATTTATGATTATCAGTTTTTGTCTCTGCCTAGCCTCATGCCACTAAAGTCTCTGAGGCAACAAAGAA TAAGCAATTTTGCTCACCTTATACAAATAAAACACAGAAAAAGGAATCACTAGAGAAATGGTACTGCA GCCTTTCTGCAGGGATTACTGCTTATTTTTAAATTACTTAAAAGGTATTGAAATTATTGTTCATAATG AGAAACCTGCCTAATAAAACAGAAAATTAAACTTAACACTTCCCTATAATGTAAACAGCTCGGTTAGG AACACAACATTACAGAAACCACTTAAGAATTGATTGTACTTGTTCTTGGAGCAGAACTAGAAGCTCAC CGTTTAGAAGCTGTGCACATTTCCCTATCAAACAGTACATAAAGTTTCCATATTCCTCAGAATCGGCT TCATTTGTGCCATGTGTTTGCTTGGAACTATGCCACAGAAAGCAGTTCTCCCCCTCAAGCTGGGCTCC TTTCATGCCGCAGTGCAAGTGTGTGATATACTGGCACCATGTGCTAATGTAGACCCATTTTTATATGA TAAGAATTAGTACGGCCTAGGGAATAGACAAGTATGTCTAAAATCCTCCCCATAGAATATGTCCCTTC CTTTAAAAGCTGTCATACTGTAAGTTCCAGCTGAGTTAAAGGCCACTGTGCTCCTATAGGGAAATATA TTCTATTGTAATTTTTACGTTCTCCAATAACAGTCTGTTCTTTGTTTACTGAAGAGAGCTTTCATGTC ATAAAATGGTGTTTTTTGACAGAGAAGCAGAATCATTGTTTTATTATAGAAATTTGCTCTTACAACAG CAAAAATAAATAGCTCATCTCTTAAGCTCCTGATCAATGTCTAACACCTCCTACCCCCAGCAACACTT CACTGCAAGTATATTAACACTCTATAATAGCAATTCCACTCACCTACCAAGAAATGATCTTCACAAAT GATTTACAGCTAAACCAGAGCTTAAACACATAGCACCCAATCAAGGGCAGATTTTTATCTTTTTCCCA GTCATATAAGTTCTGAGAAGAAATAGATTAATGTTGATCTCCCAGACAACTGCTGAGAAAATGTACAA AGGATGTTGTTTATTTTGAAGAATGAGACCTAGTTGTTAAGCACTTTTTCCCCTTATATGTACGTCCA AAGGTAACCATTACACCATTTTGATGCAAATTTAGGATATATATTTATTCATACCTCTCTTCTCCATT CGGATGTTGTCTGTGTGAGTGCTCACAGACACATGCACACATACACACATGCACTCCTGTTTCACACT TATTTGTAAAACTCACAAGGATTTCCAAGCCATTAATATAGCATTGTTTAAGGTGAACACATGGTTGT TCACCATCCATATGTATCTTCACTTTGTAGCACTCAGAATTTGGCAAAATCAGAAGGCTGAAACCTCA TGGATTAAATATATTCTATATAACATATGTCTTAATTGCTGTTACTGTAAAGAAACCTGGACTAGCCA TATTTGACTAATTTCTACCTAAGGTATTTGAATTCTTATAAATAGATTCATTGCTTTAATCACACAAG AGTGGTTTATATGAATGTAATTATCTCCACTTTATAGCTGAATAAACTGAGCCTGATTCTATCCCTAT ATGGGAAACATGAATTGAACAGCTGTGCCAATTATTTTGATAATTCAAATTTCACATCTACCATGTGA AGACAGCAGAAGAGGGTTAGGGGGCTTGAATTATTCTGATTAACTGTGTTCATGAGTGTAATCGCCTC TAGATAATCACTCATTTCTTCACTTCACTTCCCATCTACAGGTAGTATCAGCGAATGGTAACATCTCT TGCTTTGCCTCAGTTTATTGATGGCTGCCGTTAGAAATAAAAAGCATGGTTTTGTTTCAGTACTTAAA TGAATAATATCTTCAAAATGTTTTTAAAACGTGAAAAGGTTGAATGCATTTTTAACAAATGTTTTGTT AGCTTTGACTTTTATTTTTGAACAGATGAGCACAATACCCCAGTACTCCTTTCCTAGAAATAGGAGTA CTACCTGAAGACTTATTTCCCAAAGAAAAATATCAGGTCTAGTGCAGCAATACGTATTAAGGGCATTG AAAAGTTATATTCACAAAATGTGACATCATAACATATGTTAATACTTCTTATCACTGATAATAATCCT TGAAGTTGTATTTCCAGAGAGATCTCAATTTCTTCTCACACTCTGAAAGTCTCTGTTTATCCTTTAGA GTAGGAATGTAAGAATTTAACAAAACATTCTGAATGTTTACCTTTTTTCTAAACTGAAACTACAATCC CTTTTTACCCCTATATAGTAAAATATAATATTACAAGTAGAATCAGCAAATTTGTTTAATAATTCTTT GGGACAGTTTTTACAAGCAATGGGGTTGAATTTATGTTCCTTGTGTGCAGTGGAGTTATTATATTCTT CTTAAAAAGATGCATGAAGGTAAATTAGAAATGTTTTACATGTTTTCATGACAGGACATTTAATCAAA GAGGAGATACAAGAGGCTTTTCTTGGGTTACTGCAATTTAATTTTCCATTTCTTTCTTGGAAGGGACA TTGGATGCAGTTGTACGAGGTTAATATTTCTAACATGCCACTTTTATTGTGGCATTCTTCTGCTCTCA AACCTCTGATGATTTCCCATGGCCTTCAACATGATGTCCTTATTTGGGCATCTAGTGTTCTGAGCCCT CACATTCTGGCCCCAGCTTCCCTTCTCAACTTGATCACAGCCATCGTAATTCTGCTAACTAATTACAC AGCTGCCCTTCCCACTCTTTCTCAACCACTCTGCTGTATTCTGACTTCTACACTTTAGTTTTAAAGCT ACTCCTTGTCCTGAAATTCCTTCTCCCATTAGGTCATTATTAATTGAGTTCATCCTCTAAGTTACAGT TCATGTTGCTGTTCCTCTATGGCACCTTCCCTGAACCTGGTCCCATATAAAATCCCATCTCTCAGAAT CCCATTAGGGTAGGATATGTGGTCTGTAGACTATTACGTTTGTCATTTACATATTGTCTTCTATTATT GGGTAACTGCGTGTGCGAGCATGCATGGGCTGGCCTGAAGGTCACCTCCCCAACTGCATTGAAAGTTC ATCACAAGTTCAATTATTTCACTAGAGAGTCTCTTTCATGTCATCCATGAGGCACATTCCCTACTGTG ATGTGTTATGCATACAATTATTTCAATAAATATTTTCTAGCTCTTTGATTGACCAAAGCTTAATTACC TGTCAACTCTAGCCTCTTGTATCTGGAATTTCTACAGTCTTTGGATAGTATCTTTAGGATGCAAAATT AGGAGGAGTATGTACCAGGCAAACTATTACAAATAATGCCCTCAAATAGTTACATTTCACTATTCATG TCTTGTAATTTATCTTCTGCTTTGGTATTTTAGTACACTTATGATTCAATTTGCTGTATAGATTCCTC TGAATAGGGACAAGAGAATTCGTCTTGATAAGTGGAAGTTCGAAGGATTCCAAAATGATGTTATTCAA GGTAGAACAAGAAATTAATACTGAAAAAATTGAGGAGTAATAATCCCCAAATATGTACATGCGTATCT CGTTTTATTGGGTTTCACTTTATTGCACTTTGCAGATATTTCACTTTTTGTAAATTGAAAGTTTGTGG CAAGGCTGCATTGAGCAAGTCCGTCGGGCACAATTTTTCCAACAGCATGTGCTCGCTTTACGTCTCTG TGTCACGTTTTGGTAATTTGCTCAATATTTCAAACATTATTATTATTATTATATTTGT7ATGA7CTGT GATCAGTGACCTTTGATGTTACTATTGTAATTGTTTTGAGATGTCATGAACTGCACTCATATGAGATG GCAAACTTTGTGGGGTGCAGTGGCTCACACCTGTAATCCTAACACTTTGGGAGGCCAAGGCAGGAGGA TCGTGTTAGCCCAGAAGTTTGAGACCAGTCTGGGAAACAAAGTGAGACCCTGTCTTTAAAATATATAT GTAGAAAAATTAACTGGGCATGGTGGCACATGGCTGTAAGGAGCCCTGCCAGCTGCATGGGAGGCTGA CACAGGAGGATCACTTGAGCCCAGGAGGTCAAGGCGGCAGTAAGCCATGTTCACTCCAGTGCCCTCCA GCCAGAATGACAGAGCAAGACCCTGTGTGGAAAAAAAAAAAAAGACAAACATTTTTTCAACTTTGATT TTAGATTCAGGGAGTACATGTGTAGGTTTATTACCTTGATATATTACATGATGCCGAGGTTTGGAGTA CAAATGATACTGTCACCCAGGTACTGAGCATAGTAACCGATAGTTAGTTTTTCAACCCTTGTTTCCCT AGCTCCACATGAGAACACGTGGTATTTGGTATTGTGTTTCTGCATTAATTCACTTAGAATAATGGCCT CCAGCTGCATCCATGTTGCTGCAAAGGACATGATTTTGTTCTTTTTTATGGCTGCATAGTATTCCATG GTGTATATGCACCGTATTTTCTTTCTCCAGTCTGCCACTGATGGGCACCTAGGCTGACTTCATACCTT TGCTATTGTGAATAGTGCTGAAATGAGGATGAGAATACATGTGGTTTTTTAGTAAAGCAATTTGTTTT ATTTGGGCTATATGCCCAGTAATGGGATCACTAGGTTGAACGATAGTTGTGTTTTAAGTCCTTTGAGA AATCTTCAAACTGTTTCACTGTGGCTGAACTAATTTGCATTCCCAGCAACAGTGTATCAGAGTTCCCT CTTCTCTACAGCGTCAGCAGCATCTGTCATTTTTTTGACTTTTTAATAATAGCCAGTATGAATGGTGT GAGACGGTATCTCGTTGTGGTTTTGATTTGCATTTCTCTGATGTTGAGTGATGTGGAGCATTTTTTCA TGTTTGTTGGCCACTTGTATGTCTTCTTTTGAGTAGTGTCTGTTTATGTCTTTTGCCCATTTTTTTTG ATGGGGTTATTTGTTTTTGACTTGTTGAATTGTTTAAGTTCCCTATAGATTCTGAATATTAGACCTTT GTCAGATGCATAGTTTGCAAATATATTCTCTTATTCTGTAGACTGTCTGTTTACTCTGTTGATAAATT CTTTCACTGTGAAGAGCTCTTTAGTTTAATTAAGTTCCACTTGTCAATTTTTGGTTTTGTTATAATTG CTTTTGAGGACTTAGTTATAAATTCTTTCCCAAGTCTGATGTCCAGAGTGGTGTTTCCTAGGCTTTCT TATAGGATTCTTATAATTTGAGATCTAATGTTTAAACCTTTATTCCATCTTGAGTTAATTTTTGTATA TGGTGTAAGGAGGGGGTCCAGTTGCATTCTTCTGCATATGGCTAACCAGCCATCCCAGCATCATGTCT TAAATACAGAGTCCTTTTCCCATTACTTATTTTCATAAGATGGCAAACTTAATCAATCAATGTTTTGT GTGTTCTGGCTACTCCACTGATCAGCCATTCCCTCATCTCTCTTCCTCTCCTTGGGCCTCCCTATTCC CTGAGACACAACAATATTGAAATTATGCCAGTCAGTAACCCTACAATGTCCTCTAAGTGTTCATGGGA AAAAAAAGAGTCACATGTTTGTCACTTTAAATCAAAAGTCAGAAATGATTAAGATTGGTGAGGAAGGC ATGTCAAAAGCCAAGACAGGCTGAAAGCCAGACCTCTTGTGCCAGTTGGCCAAGTTGTGAATGCAAAG GAAACGTTCTTGAAGAAAATTAAAAGTGCTACTCTGTTGAACACAGGAATAAGAAAGTGGAACGGCCT TATTTTTAATATGGAGAATGTCTTAGTGGTCTGGATAGAGGATCAAAACAGCCACACCATTATCTTAA GCAAAAGGCTAATCTAAAGCAAAGGACTAATTCTCTGCAATTCTGTGAATGCCGAGAGAGGTGAGGAA GCTGCAGCAGAAAAGTTGGAAGCTAGCAGAAGTATGTTCATGAGCCTTAATGAATAAGCCCTCTCTAT AACATAAAAGTGCAAGGCAGAGCAACAAGTGCTGATGGAGAAGCTGCAGCAAACTATCCAGAAGATCA AACTAACATCTAAGTTAATAAAGGTGGCAATACTAAACAACACATTTTCAATATAGACGAAACAGCCT TCTATTGGAAAAGGATGCCATCTAGGACTTTCATAGCTAGAGAGAAGTCAATGCCTGGCTTCAAAAGT TCAAAGGACAGGCTGACTGTCTTGTGAGGGGCTAATGCAACTGGTGACTTTCAGTTGAAGCCAGTGCT CGTTTACCATTCCAAAAATCCTAGGGCCCTTCAGGTTATGCTAGATCTAGTCTGCCTATGCTCTGTAA ATCAAACAACAAAGACTAGATGACTGCACATCTCTTTACAGCATGGTTTGATGAACATTTTGAGCCCT CTGTTGAGACCTACTTCTCAAAAAAATGTGTCTTTCAAAATATTACTGCTCTTTGACAATGTCCCTGG TCACCCAAGAGCCCTGAGGAATATGTCCAAAGAGAATGATTTTATTTTCATACCTGCTAACACAACAT CCATTCTGCAGTCCTTGGATCAAGAAGTCACTTCAACTTTCAAGTCTTATTACTTAAATCATACATTT CATAAAGGTATAGCTGCTATATTGTGGTGAGTCCACTGATGGATCTGGATAAAGTAAACTGAAAACGG AAAGTCCTCACCATTCCAGATGCCATGAAGAAAATTCATGATTGAGGGGAGGAGGTCAAAATATCAAC ATTATCAGGAGTTTGGAAGTAGTTAATTCCAACACTCATCAATGACTTTGAGGGTCCAAGACTTCAGT AGAAGAAGTCACTGCAGATGTGGTAGAAATAGCATGAGAACCAGAATGAGAAGTGGAGTCAGAAGGTG TGACTGAATAGCTGTAATCTCAAGGTAAAACTTCAGCGGATCCAGAGTTGCTGCTTATGGATGAGCAA AGATTGTGGTTTCATGAGATGCACTCTACTCTTGGTGATGATGCTGTGAACATTGTTGAAATGACAAC AAAGGATTTAGAATATTCCATAAACTTAGTTGATAAATTAGCATCAGGGTTTGAGAAGATTGACTCAA ATTTTGAAAGAAGTTCTACTGAGTAAAATGCTATCAAACAGCATCACATGCTACAAAGAAATCATTGG CTATAAAGGAGAGCCAATCGATGCAGCAAACTTCGTTGTTGTCTTATTTTAAGAAATTGCTACAGCCA TCCCGACCTTCAGCAACCGCCACCCTGATCAATCAGCAGCCATCCTCACTGAGGCAAGAGCCTGTACC AGCAAAAAGATTATGACTCCCTGCAGGCTCAGATGATTGTTACCATTTTTTTTAGGAGTAATGTATTT TCAAATTAAGGTATGTACATTTTTTAGATACAATGCTATTGCACACTTGACAGATGATAGTAGAGTGT AAACATAACATTTAATGCACTGGGGAACCAAAAATATTCGTGTGCCTCATTTTATTGTGATATTTACT TTATTGCAGCAGTCTGGAACCAAACACACAATATTCCAAGGCAGTCCTATATATTGTTTCATGTCTCT CTTTCTTCTAAAATGTGTGTAGGAGAAAAAATTATATCACTTATGTTACTGGGCCATAATATCAAAAG CCTGCGAATCTGATGCACATGATAAAAACTGGTCTTAAACCTGTCTTGATTATCCTTTGTTAATATGC CAAATTTATAGAACAATAGAGTTTCAAGAAATGTGAACAATGTAGAATAACTAAAAGATCTAACGTTG AATAGCTAAAATTATCAACGCCCTTTATATCACTTTAGAAATGCGTTTGCAAATCATTATCAACAAAT TGTAGCATAAAATTCTTTTTTTTTCTTGACTTTGAAATTGTATTTCAAGATCCGCAATTTACACCACA TTATTTACTTACTGGCTTGTGAAAGTGAAAGGCATTTTCATTTTTGGATGTTAAGGGTTTTAGTAAAT GACAAGTAAATCAATCCTTTAAGTTCCGTGTGGTATAATAGCTTGGAAAGGACCATCTTAATCTTTTT TTCAACACAGGGAGATAATTTATTTTAAAAATAACACACTAATAGTAGATTAATATTATTACCATTTC AAAGAAGTCACCAAATTTGGTAGGCTTAAGAGGTTTTTTTTTTTTTTTTGAGATTACTATGCTCTTTT TTTATTTTATTTATTTTATATTTATTTATTTATTTTTTAGTTTTTTAATTTTACTTTAAGTTCTGGGA TACATGTGCAGAACGTGCAGGTTTGTTACCTAGGTATACATGTATCATGGTGGTTTGCTATACTCATC AACCCAACATCCAGGTTTTAAGCCCCCAATGCATTAGGTATTTGTCCTAATGCTCTCTGTCCCCTTGC CCCTCACCCCTTGACAGGCCCCGGTGTGTGATGTTCCCCTCCCTGTGTCCATGTGTTCTCATTGTTCA ATTCCCACTTACGAGTGAGAACATGCAGTGCTAGGCTTAAGAGTTTTTTTAACTCCCCAAAATATCAA CAAATTGAAACATTACTACAAAGAAATAGAGAAATAAATTTCACTGACTGTCTTATTGTTTTTTAAGT TTGAATAGCTAATAATGATTTCTTAAACAGCTATCATATTTTTTATTTTTAAAGCTAGCCAAATGATC AGTGATTTTTATAATACTGATAAATACTGCTTAGAAAAGGAACATGTGTTCTAGCAATTTCCACACAT TTCTGATTCTAATTACTTGTTTCTTTTTGTTTTATTTTTATATTTTTAAGTTTTGTGAGTACCTAGCA GGTGTATATATTTATTTGGTACTTGAGATGTTTTGATACAGGCATGCAATGTGTAGTAAGCACATCAT GTAAAATGGGGTATTCAACCCCTCAAGCATTTATTCTTTATGTTCCAAACAATCCAATTATACTCTTT TAATTAATGTAAAATGTACAATTAAATCATTATTGGTTATAGTCCCCCTGTTGTGCTATCAAATAGTA GGTCTTACTCATTCTTTCTAACTAATTTTTTGTACCCAGTAACTATACCTACACCACCCCCACCTCCC CACGACCCTTCCCATCCTCAGGTAACCATCCTTCTACTCTCTATGTCCATGAGTTCAATTGTTTTGAA TTTTAAATCCCACAAATAAGTGAGAACATGCAATGTTTGTCTTTCTGTGTCTGATTTATTTCACCTAG CATACTGACCTCCATTTCCAACAATGTTGTTGCAGATGACAGAATCTCATTCTTTTTTGTGGCTGAGT AGTATTCCATTGTGCA7AGGYACCACATGTTCTTTGTCCATTCATCTACTGATGGACACTTAGGTTGC TTCCAAATCTTGGCTATTGTGAATAGCGCTGCAATAAACATGGGAGTGCAGATATCTCTTCAATATAC TGATTTATTTTCTTTTGGGTATATACCCAGCAGCGGGAATGCTATATTATATGGTAGCTCTATTTTTA GTTTTTTGAGGAACCTCCAAACGGTTCTCCATAGTGGTTGTGCTAATTTACATTTCCACCAACAGTAT ACAAGGGTTCCTTTTTCTTCACATACTTGTCAACATTGGTTATTGCCTGTCTTTTGGATATAAGCCAT TTTAACGGGAGTGAGGTAATATGTCATTGTAATTTTGATTTTCATTTCTCTGGTTATCAATGATTCAG TGATGTTGAGCACCTTTTCATATGCTTGTTTGCCATTTGTATGTATTCTTGATCTGCCACAAGTCTCT AATTACTTGTTTCTTGTACCACTGTTTCCCTTCATTGTAGTCAGTGATTTGGTCAATCAACACTTTTT ACGTATGGGTATCTGTTAACTGTATTTCTAGGAATGGACCAAGAATTGAGAAATTTATCCCAACCAGA AAGAACAAAATCTATGGAGGCACAGGATTACTGAAAGCTTTGCTCCTATAGCCTCAGTTTTTTTCTGC AAGTTCGCTGCTTCCCAGTTGTCCTTGTGATAAAATTCAAAACCTCAAACTGATTTTTAAAAAGCCAA CTATATACTGCTTCTACTATGTCTACCTAAACTTATTTGCCATTATTTGTAAAGAATTCCAGGCTCTA ACCAGCCCATTTGAGGCTTTATTTTACGTTCATGCCTTTGTTCATGTCTGTCTTTCCCTTATAATGCT CTTCTCATTCTCTAGCCAAATCTGCCAAAGTTCAGCTGTAGTGCCATACTTGATATGAAGTCTTTGCT GAGAATTCCCATATGTGGTCATTTCCTTCACTGATTTGTTTCAATAGTTGTTGCCATTATTATTATTT TTTTTATACTGTTGCTGGATACTTTCGCAGATCCAATCTCTAACCTGTTGTTCTACCCTAGGAGGTTG ACCAATATGGCAGTAGCATTGGGCTTGCTTGTCTATTGGCTTGGTCCTTGTGTTGGGAGGCATCAGCA GATCAATGGATGAGAGGAGAGTGAGTCGAGGGATGGCTAGGTTCCTTTACTCACAGCCCCAGCTCCTG TCAAGAGGTCTTGTCCCTGCAGCCACTTCTCAGATTCTACTAACTATACCCTCCCCTTAGCCTTTCAG GCCTTGAGGAGGAAAGCCTCCTCATCCCACTTTGAATGAACTATTTATTGCAAGAACCATGACTGATT CAGAATATAATCTGTCCTTGAATGAAATAGTTAATTTCCCCTTTTGTATTCTCGTTTCATATCCCTGT CCCTTTATCCATTCCTATATTATATCATACTATCATATAGCTACCTTATATTATACTATGACATGAGT ACCTTGTAAGTATATCATGCTATATTATAGTTCTTAAGTGTGTGGGCTTTGGGGCCAACTTACCTATG TTAGAAGTTCTGCCACTTATTACCATGTGATCCTAGACAAATTGTTTAACTTCTTTTTCATTCATTTT CTTTACTAGTAAAATAGGGGCAATATTAGTACCCACCTCACAGAGTAATATGATAATTACATTGACTG ATAGTTTTTATTTAAAACTTTTATTGTTCTTACTATGAAATGGGAAATGTTCTAAACACCTTACAAAT ATTAACTCTATTAATTCTCATAATGAATCTGAGAGGTAGAGACTCAGTATCTCCATTTCACAGTGCTG GAAATGATACAGACAGCATTTAAGTAACATACTGAAAATAGTAAACCGAATAGGTGGCAGCCAGTATG CAAATTGGGAAAGCCTGACTCCAGAGTTCATTCTTTTAACTAGTATGCTGTGATAGACTCTTTTGGCA TATGGTATGCACTCAATAAACAACTATTGTTGTTGTCGTTAGCATTACTTCCCATTGTATTATTACAC AAAAAATAATTGTTTATGAGTATTTGTTTGCTAGATTATAAGTTCCTTGAAAAAAGAAGACAAGTTTT ATTTGTCTATGTGTACTAGCTGAGTGCTTGGCAAATAGTTGCAGTTTAGTAAATGTTTCTAAAACAAA TTATTAGTTGTTTCTTATGTATTTCCCAAGTCTATCCTAGCCTTGGAAACAGCTAACACTTAGCTAAA CCTAGAAATGTCATTTGAGATTTCAGCAGCCATCATTGTTGCTGAAGCCACAGGTTCTCCTTTTTATC TCCAATTTCTTCCTCAGATGATTCACCACTTTCTTTGTCGTTTCCCTACTTCATTTTTCCTATAGTGA CTTTTGTTCTCCAATAACCATTGATAGTGATGACAGTCCCACCTTGGAACCACTTCTAACTGTCCTGT TCAGCTTTTCCTGAGGCCAGATTTCCCCCAAAATACATTTTTTAGCTTCATAACTGCTCCTTCCAGAA ATTTGAAACGCATTCTCAGGAATTAAGCAAGAGGCATTTGATTGACGTCATTTAATTTGTGTTTAAAT GTGTTCTTCCCATCAACGATTAACCAGTGCTTCAGCCAAGATACATAACTTTTATTCTCCACTAACCT TAGGGTTGAGGTCACAATCAGGTACGTAATCTGTAGAGCCCAGTGAAAAATGAAAACGCAGGGCCCTT GGTTAAAAAAAAATTAAGAATTTCAAGATGGCAACAGTAGAGCATGAAACCAAGTATGAATCCCTTCT AATGCAGATCCTTGTGTAACTAACTGCACAAGTTATACGTTCAAGAAGCTGGTCCTGGTTGAGGTCTT TGTCTACCTAGGGCACTTCTCACTCAGAGAGGTGGAATAATCTTAACTTTCTGTCTTCCGTCATCTGA AAACTTGCCCCAAAGTTCCTTTTGCCATCTCTTGCAGCAAACCTAGTGGTTGTTATCTGTTAAGGATT CCTGGTGGCTTGCTTTAGTTTCCTACAGTTCTTGAGCTGCATGTGTTGAATGGAACTCCACCATTACC ATGTAACACATCTGAATACTCTTATTTTCCTCCAGTTAAATTCTGCGCTCCTTGGAAATAATGGTCAT GCACCCTACCTTAGTGATTTCTAAATAGAGGTAGTATGTAAAAATACATATTTACTTGAATTGCATCT TAAGAGGCCAGCCCATGGGAGGCATGAAGAAACCTATGTTACTAATTAATATTCAATAATTGACAGTT ACACATTCAGGTAGTAGTGTCATGGAACCATCACGTTACATGGAACTGAAGAGCTGATGAGAGGTTTA GGGTCTAGGAGGACAAAAGTGAGTGTATTAGTCAGGGCCTGAGGTTATATGTACCCAGACAGGATAAA ATGGGACAATATTTTATTAGTGGAAATATCTATGTGAAAGAAAAGAAGGAGGAAGCCAAGGAAGGTGC AAGAGATGTTAGATCAAGATGCAATTCTGACTCTGCAAGGAAGAGAGAGGGAGAGAAGGCTAGGCAGA AGCATCCCAGTGTGCGGTCTAGTGGAAGGAAATTTTGGCAAAGCTGTTGGGAAGTCATTGAGGCAGAG CCAGGCAAAGAAGTCCCATGTCTCCCAAGGAAGGCTCTCTGCCTTAGTATTCCCACCACACCCAATCA TTGGGTGAGGAGAAGTCTGTGAGAAGCTTGGCTTTGGTGCAGTGCAATCATGGATTTCAAAATGCAGT AACAGGAGTCCTCAGTCAGTTAAGACCCAATAATAGAAGGCCTGCATATTCTCATGGTGGCCACTTGG GTATGAGGAGCAGTGGTGTTTAAAACTGTTTTGTATAATTTAAATAAAGAAAAGCTGAGGACTACTTA AGCTTGATTCCTTCAGAAGACAGTCTTTGGCCTTTATATTTCATGTGATATCTTTGCCATATGCTCTG ATAACTCTCCATGTTTCCCCTACCATAATACCTCAGGTTGTTGCAATTGCTTTTTTATTGCCTGTCAT CACTACTCGTTTGTTTTCTCTTTGAGAACAGGAATTATTTTCTCCTTCACTGCTACAGCCCCTGCACC TAGCTCAATGAGTGACACAACAGAAGCACTTAAAAAATTGCTATAACTCAAATTTGGGGGATATTCTA CAAAATACCTGGCCTCTGTTGGTCAAAACTGTAAGTGTTATAAAGTTCAAAGAAAGGCAAATAACTAT TTCAACTTAAAAAAGACTAAGGAGATACGACAACTAAAAGCAATGCGTGAGTCTGGACCAGACCAGGA AATAAAAATATAGCTATAAAGTTCATTAATGGGGTAATTGTCATACTCTGAATATAGAGTATGGATAA GATTATGGTACTAAAGCCACGCTAAATTTCCTGACTTTGAAACTGAGCTGAGGTTATTTAAGAGAATG TCTTTGCTATTAAGAAATAAAACCTAAAGTATTTAAGGGTAAAGGGGCATGATATCTGCAAATTATTC TCAAATGATTCAGAAAAAAAATATATATATATAAAACATTACATATACAGTTATATATCTATACACAC AGAGAGAATGATAAAATGATAAATAATTAAAAATAATGTGGCAAAATGTTAACAAATGGTGAATCCGG GCAAGGGTTACCTGGGAGTTCTTTATCTTGCAAATATTCTGCAAGCTTGAAATTATATAAAAATAAAA TGCATCTTATAAAGTATTTATTCAGTGAATAAAGAACAAAAAAGGCTAACTGCAGTTGGAAGATATTT ATGAAGTTGGTTATGAAGATTCTTAAGAAGTTACCGATGGAGGTGCTAGTAGAACATTCAAAAAAGAA GTAGGGAAGGTTGACCAAGTAGGAAAATATCAATATCCAAGCCAGTATAAAATGGAAATGAGAAGTGA GGAAGTAAGTGGAAGACAATGAGGATGGTTTTCGATTTGGCCACTCTATTTGGAGAGGCAGCCGAATG CAAGAATAGAAGCCAGAAGAAGATGCTCAGTGAGATGGTTGAAAGCTAGATAGATTACAGCATCCTCA CCAGTAAAACCCTTTCGGTAACTAGAAAGGCTACAATTTAGTACCTTCCTGACTTCTATGCTTATTTT CTTCAATACATAAAATGGTTCCGTAAACTCTTTTACCTTCTGAATTCTTTATATTAATTTTTTGAAGT TGTAAATAAAATAGCATCAGTTCTACATTGTTACATTTCAGCTTAATTCATATTCATTTACTGAAAAT GGGAACATTTGAAAAATCATCATGGGCATTTATGCTATGTAGATTGTTGATTTTTATAGAAAAATATA AAAATATGACCAGTTTGATTTTCAAAGTCTTTTCTTAGACATGTAAATACTAAGCATTCAACTCAACA TATAGAGTTTTTATTTGAGTATTATTTAGGTGGAATTCTATTTTAATGAATACAATAAAAAATTGTAA TTTTGTCTAAAAGCCTAAAATGCCCTAGTTATAATATGTATGATTTCACTGTTTAACTTCCTATTTCA TAGGGTTGCTATTTATAACCACTTCACTCAACTCTGGGGGGACTTAGTGAGATTAAAGACTTCTGATT CACTTTGTATTTGAAGAATTTTTTTTCCTCCATCTTTGCTCAGCTAGTGGAATCCATGATGAATTCTC ATCTCCAAGGGGTAAGCAGTTTTTAGTAAAGCCCAGTAGCTGACTTATGACTCCTTAGAAATAGCATT GATTCCTTCCTTCTCCTGTGTTTTGTTTCCTCTAGAATGATAGAATCCATGTAGACACGATCCATTAT CATGCTTAGGTACTGGTAAGCATGTAATGATTTTAGTTTTGTTCGCTTTAAGTTATTTGTGTCACAAA TATCTGGGATCATATCAGAGAAATAAATAAGCACAATTAGCATTCTACTTGTTTGTTATGACTAAAGC TAGGTTGAGGAAACAGAAAAGGACCAGAGGTCATATGAGGATGAAGATAATACTAGGAACAGCATGTT TGGGAGAGTAACATCTGGTAGGGGTAGCAGATTGGGGGCAGAGAACAGAATTTTATAGATGGATATTT TGGAGGCAAGTAGTTTGAGTAATGATTAGATCTAAGGTGTTTTCTCATCTGTGGGTGGCTCGAAGGAA TAGAGGTGAAGGTCAGTTTATTTGAGAAGTTCTGGAATTATAAAACTAAGTTGAAGTCAAAGAAAGTA TAGTAGCAAATAAATAGAATACCCTTAAAAGGAAACCAAATGAAAAATAATCGTTACTCTCACCATAT GCTTGTGTTCTTATTAGCAAGAAATTCTTTTAACCACTGTTTTTATAATATCTTAATGAAAAAATACT GAAGCGTATGCCATATTAAATCCCTCTCTTTATTTCTAGAAAGGGAATCAAAGGAGAAAATTCCCATT CTGCTATACTAAAAGACCACTAAGTAAAGAGCCTATTAGTGTATGATAAATCCCATAGCAATATACAT TATCATTTTACAGCTTCTTTGTTGAAATGAATGTTTGTATGTGTTGACCATAGAGTGGGATAAAAAGT TGAAATTTTGTTTTGAAATATTTTAGAAATGCATAGTTGTACTGCAGTTGTGAACCTCCTTAGATTTT TAAGGAGGCTGCTTCAAAGGATCTCATTAATAATCTTCTCAGGTGCTTACAAAGCATGTGTCTGTCAG CAGAATTAGAGAATCACCCAACTAGAGAACAGGTTTCACAATACCCTGAGACCTATTTTGTTCATTAG AGAGGAAAATGGCTTGTTTTGAGTCTAAGTTGACATGCTTGCTAATTTCAGCAATAAAAGCTGTTCAT TGTGGTCAGGTTTAATTTAGAGCCTGGTAAGGTTCAGATTAAAGTTGATCAACTTACTTTTACAACAT ACTTCTTAAATGAACTTTGAAATCTTAAAAGAAGGAAAAAAGTATAGCAAACAGTGAATAATGTATCT AAAACTGAGAAGCAAAAAAAATCTGGTTATGTGAGAGTGAATTAAAAGAAGAACAACCCAATAAAGAT AATCTTTGTTATATAAAAATTTCCAAGTATCGAAAAGCACGATTTTTCATGTGAGTTACACACTATAC CGAATATATTTGTCCACTGCCACATGCATAGTCCCTAGAATAGTGCCTAGTGCTGAAAAATATTTATT AAAATGAATGGATGAGTAAATGAATTTATGTATTTTGCCAGCCCTGTGTATTTAAAGTTCTCTGTTAA CTTTGAGGTGAAAATTTGACTTCATCTGAGGTTTCTGGGTAAGTCCGTTTTAAAAATTCTATTGAACA TATTCAAACATTTTAGGGTAGGCAATTCCAAAGCAACCTTTCAGCTTCCCATGTCACAGATGACCAGA GTTTCACATTCTAACACTGGAAAACATCTTATTTCATAAAATCTACCTGCTACTATATGGTTCCTACT TTAAAATTTGTTCAGTACTCTCCAGCTGACTTATGCCACTTACTTCAATAGCTGTCTTTGGCAATTTG TTCCATATTTCAAACACTCTGTTGTGTAAAGAAACCATAAAAGTTAGAAACCTGAAAATTGGATTTTT TTTCTGAGCAATCACAGCTTACAAATGTGGAAAATTTGTTAAAAGTTAGCCCCTCCAATTTTTCAATA CAGAGAGGAGAAAGTGCCTAAAGTAGATGTACAATGTTTGGAAAAGTTTTTTGCATTATTTTACTATT ACCAAAAGCAATTGAGTTTAAATCACAAAGCCTGTCTCCCTACCTCTTCACAGAAGAAACACTACAGA ATGATCAAAATTTGGCCTTTCCAAAACCAAAATTCGTTAGAAAATCAGCAGGAGTCAAAGTACAGAGT AAATAACTAAGTTTCATATAAGTTTCAGATACATTACTATCTACCACTTTCATCTCTTCATCTTCATT GGCCTCATGTGGTAGAACATCATATTTAAAATTATACAAACTTGCTGGCTTGTTTACTAGTGTGGTTA TTATAAGAAAAAAATGAGAAAATATAGATAAAACATCTGTCACATATTGCTTATAAACTAACAGTAAA TATTACTTGTATTTTCCCCAATTAAAATAAAATTTACTGAGTTTTAGAACCAGAGCTAGTCAGATGCC TTTTTTTCATAAATTTCTTCATAAATACCTCTGAGATTGTGGTCCTTAAATCTAGAGAGACTAAGATG ACAGAGAAAATAGACACTGAAGAAAGGGAAGAATATCTTAATGATTTACATTACTACCTATAAATTAA AAATTGTTAACTTTATTATATTTGTATTTTTATTTAAAATAGTGCTATATTAAAGTCATTTATAATAC AGGGGAATAGGAATACTAACCTGTAATCTGATGCTCTCCAAACTTGCCTAAATCATAAAAGTTAATTA GATAATTTATTTAAAATGCAAGATTTGCAGCCCTTTCCACTACATATTCATTAGTTCTGGAGGGAGGC AAAAAGGTTTGGTGATTCTTACGGACAGGCAGCTTAGGAGAAAAGCTGATTTAGCTCGTCTACTTCAC CTTTTCATTTGACAGGTGAGAAATCTCAGGGGTACAATGAAGTTAAATAAGTAATATCTCTTAAATCG GTTCTGTGCTTTTTCTGTTTTTAAAATAAATATACCTTAATTTTGACGTCACACAGAATGATATTATA AGTATAAATAGTTATCTATCTTTTAAATACATTGTCGTAATTCAGAATAACATTTCTTACTCAAGGCA TTCAGACAGTGGTTTAAGTAATCCGAGGTACTCCGGAATGTCTCCATTTGAGCCTTTAAATGAAGAAA ATCTATAGTCAAGATTTTCATTTGAAATATTTTTGATATCTAAGAATGAAACATATTTCCTGTTAAAT TGTTTTCTATAAACCCTTATACAGTAACATCTTTTTTATTTCTAAAAGTGTTTTGGCTGGTCTCACAA TTGTACTTTACTTTGTATTATGTAAAAGGAATACACAACGCTGAAGAACCCTGATACTAAGGGATATT TGTTCTTACAG SEQ ID NO: 129 AAV portion including U6-g7 expression cassette and Ex52 donor: U6 PROMOTER, 

  PAM (ATTCCT) , SaCas9 gRNA SCAFFOLD, donor sequence, exon52 AGGGCCTATTTCCCATGATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATA ATTGGAATTAATTTGACTGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTA ATAATTTTCTTGGGTAGTTTGCAGTTTTAAAATTATGTTTTAAAATGGACTATCATATGCTTA CCGTAACTTGAAAGTATTTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACC G 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCA AAATGCCGTGTTTATCTCGTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGT ACAAAGTTGGCGTTTAAAC 

gttaatttgcgttcta gccaccgagatacagtaacatcttttttatttctaaaagtgttttggctggtctcacaattg tactttactttgtattatgtaaaaggaatacacaacgctgaagaaccctgatactaagggat atttgttcttacaggcaacaatgcaggatttggaacagaggcgtccccagttggaagaactc attaccgctgcccaaaatttgaaaaacaagaccagcaatcaagaggctagaacaatcattac ggatcgaagtaagttttttaacaagcatgggacacacaaagcaagatgcatgacaagtttca ataaaaacttaagttcatatatccccctcacatttataaaaataatgtgaaataattgtaaa tgataacaattgtgctgagattttcagtccataatgttaccttttaataaatgaatgtaatt ccattgaatagaagaaatac 

SEQ ID NO: 130 AAV portion including U6-g7 expression cassette and Superexon donor: U6 PROMOTER, 

  PAM (ATTCCT) , SaCas9 gRNA SCAFFOLD, donor sequence, exon52-79 cDNA coding sequence, 

AGGGCCTATTTCCCATGATTCCTTCATATTTGCATATACGATACAAGGCTGTTAGAGAGATA ATTGGAATTAATTTGACTGTAAACACAAAGATATTAGTACAAAATACGTGACGTAGAAAGTA ATAATTTGTTGGGTAGTTTGGAGTTTTAAAATTATGTTTTAAAATGGAGTATCATATGGTTA CCGTAACTTGAAAGTATTTCGATTTCTTGGCTTTATATATCTTGTGGAAAGGACGAAACACC G 

GTTTTAGTACTCTGGAAACAGAATCTACTAAAACAAGGCA AAATGCCGTGTTTATCTCGTCAACTTGTTGGCGAGATTTTTTTCTAGACCCAGCTTTCTTGT ACAAAGTTGGCGTTTAAAC 

gttaatttgcgttcta gccaccgagatacagtaacatcttttttatttctaaaagtgttttggctggtctcacaattg tactttactttgtattatgtaaaaggaatacacaacgctgaagaaccctgatactaagggat atttgttcttacaggcaacaatgcaggatttggaacagaggcgtccccagttggaagaactc attaccgctgcccaaaatttgaaaaacaagaccagcaatcaagaggctagaacaatcattac ggatcgaattgaaagaattcagaatcagtgggatgaagtacaagaacaccttcagaaccgga ggcaacagttgaatgaaatgttaaaggattcaacacaatggctggaagctaaggaagaagct gagcaggtcttaggacaggccagagccaagcttgagtcatggaaggagggtccctatacagt agatgcaatccaaaagaaaatcacagaaaccaagcagttggccaaagacctccgccagtggc agacaaatgtagatgtcgcaaatgacttggccctgaaacttctccgggattattctgcagat gataccagaaaagtccacatgataacagagaatatcaatgcctcttggagaagcattcataa aagggtgagtgagcgagaggctgctttggaagaaactcatagattactgcaacagttccccc tggacctggaaaagtttcttgcctggcttacagaagctgaaacaactgccaatgtcctacag gatgctacccgtaaggaaaggctcctagaagactccaagggagtaaaagagctgatgaaaca atggcaagacctccaaggtgaaattgaagctcacacagatctttatcacaacctggatgaaa acagccaaaaaatcctgagatccctggaaggttccgatgatgcagtcctgttacaaagacgt ttggataacatgaacttcaagtggagtgaacttcggaaaaagtctctcaacattaggtccca tttggaagccagttctgaccagtggaagcgtctgcacctttctctgcaggaacttctggtgt ggctacagctgaaagatgatgaattaagccggcaggcacctattggaggcgactttccagca gttcagaagcagaacgatgtacatagggccttcaagagggaattgaaaactaaagaacctgt aatcatgagtactcttgagactgtacgaatatttctgacagagcagcctttggaaggactag agaaactctaccaggagcccagagagctgcctcctgaggagagagcccagaatgtcactcgg cttctacgaaagcaggctgaggaggtcaatactgagtgcgaaaaattgaacctgcactccgc tcactggcagagaaaaatagatgagacccttgaaagactccaggaacttcaagaggccacgg atgagctggacctcaagctgcgccaagctgaggtgatcaagggatcctggcagcccgtgggc gatctcctcattgactctctccaagatcacctcgagaaagtcaaggcacttcgaggagaaat tgcgcctctgaaagagaacgtgagccacgtcaatgaccttgctcgccagcttaccactttgg gcattcagctctcaccgtataacctcagcactctggaagacctgaacaccagatggaagctt ctgcaggtggccgtcgaggaccgagtcaggcagctgcatgaagcccacagggactttggtcc agcatctcagcactttctttccacgtctgtccagggtccctgggagagagccatctcgccaa acaaagtgccctactatatcaaccacgagactcaaacaacttgctgggaccatcccaaaatg acagagctctaccagtctttagctgacctgaataatgtcagattctcagcttataggactgc catgaaactccgaagactgcagaaggccctttgcttggatctcttgagcctgtcagctgcat gtgatgccttggaccagcacaacctcaagcaaaatgaccagcccatggatatcctgcagatt attaattgtttgaccactatttatgaccgcctggagcaagagcacaacaatttggtcaacgt ccctctctgcgtggatatgtgtctgaactggctgctgaatgtttatgatacgggacgaacag ggaggatccgtgtcctgtcttttaaaactggcatcatttccctgtgtaaagcacatttggaa gacaagtacagataccttttcaagcaagtggcaagttcaacaggattttgtgaccagcgcag gctgggcctccttctgcatgattctatccaaattccaagacagttgggtgaagttgcatcct ttgggggcagtaacattgagccaagtgtccggagctgcttccaatttgctaataataagcca gagatcgaagcggccctcttcctagactggatgagactggaaccccagtccatggtgtggct gcccgtcctgcacagagtggctgctgcagaaactgccaagcatcaggccaaatgtaacatct gcaaagagtgtccaatcattggattcaggtacaggagtctaaagcactttaattatgacatc tgccaaagctgctttttttctggtcgagttgcaaaaggccataaaatgcactatcccatggt ggaatattgcactccgactacatcaggagaagatgttcgagactttgccaaggtactaaaaa acaaatttcgaaccaaaaggtattttgcgaagcatccccgaatgggctacctgccagtgcag actgtcttagagggggacaacatcgaaactcccgttactctgatcaacttctggccagtaga ttctgcgcctgcctcgtcccctcagctttcacacgatgatactcattcacgcattgaacatt atgctagcaggctagcagaaatggaaaacagcaatggatcttatctaaatgatagcatctct cctaatgagagcatagatgatgaacatttgttaatccagcattactgccaaagtttgaacca ggactcccccctgagccagcctcgtagtcctgcccagatcttgatttccttagagagtgaag aaagaggggagctagagagaatcctagcagatcttgaggaagaaaacaggaatctgcaagca gaatatgaccgtctaaagcagcagcacgaacataaaggcctgtccccactgccgtcccctcc tgaaatgatgcccacctctccccagagtccccgggatgctgagctcattgctgaggccaagc tactgcgtcaacacaaaggccgcctggaagccaggatgcaaatcctggaagaccacaataaa cagctggagtcacagttacacaggctaaggcagctgctggagcaaccccaggcagaggccaa agtgaatggcacaacggtgtcctctccttctacctctctacagaggtccgacagcagtcagc ctatgctgctccgagtggttggcagtcaaacttcggactccatgggtgaggaagatcttctc agtcctccccaggacacaagcacagggttagaggaggtgatggagcaactcaacaactcctt ccctagttcaagaggaagaaatacccctggaaagccaatgagagaggacacaatg 

tcagcctcga 

 

 

 

gtaagttttttaacaagcatgggacacacaaagcaagatgca tgacaagtttcaataaaaacttaagttcatatatccccctcacatttataaaaataatgtga aataattgtaaatgataacaattgtgctgagattttcagtccataatgttaccttttaataa atgaatgtaattccattgaatagaagaaatac 

SEQ ID NO: 131 Streptccoccus pyogenes Cas9 (with D10A) MDKKYSTGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTA RRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIY HLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINAS GVDAKAILSARLSKSRELENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYD DDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVR QQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNG SIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPW NFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYETVYNELTKVKYVTEGMRKPAFLSGEQ KKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEEN EDILEDIVLTLTLFEDREMIEERLKTYAHLEDDKVMKQLKERRYTGWGRLSRKLINGIRDKQSGKTIL DFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELV KVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYL QNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWR QLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIRE VKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLS MPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKK LKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGN AYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRI DLSQLGGD SEQ ID NO: 132 Streptccoccus pyogenes Cas9 (with D10A, H849A) MDKKYSTGLAiGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTA RRRYTRRKNRTCYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIY HLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINAS GVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYD DDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVR QQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNG SIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPW NFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQ KKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDHEEN EDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKOLKRRRYTGWGRLSRKLINGIRDKQSGKTIL DFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELV KVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYL QNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWR QLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIRE VKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRK MIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLS MPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKK LKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGN ELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLS AYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTTDRKRYTSTKEVLDATLIHQSITGLYETRI DLSQLGGD SEQ ID NO: 133 Polynucleotide sequence of D10A mutant of Staphylococcus aureus Cas9 atgaaaagga actacattct ggggctggcc atcgggatta caagcgtggg gtatgggatt attgactatg aaacaaggga cgtgatcgac gcaggcgtca gactgttcaa ggaggccaac gtggaaaaca atgagggacg gagaagcaag aggggagcca ggcgcctgaa acgacggaga aggcacagaa tccagagggt gaagaaactg ctgttcgatt acaacctgct gaccgaccat tctgagctga gtggaattaa tccttatgaa gccagggtga aaggcctgag tcagaagctg tcagaggaag agttttccgc agctctgctg cacctggcta agcgccgagg agtgcataac gtcaatgagg tggaagagga caccggcaac gagctgtcta caaaggaaca gatctcacgc aatagcaaag ctctggaaga gaagtatgtc gcagagctgo agctggaacg gctgaagaaa gatggcgagg tgagagggtc aattaatagg ttcaagacaa gcgactacgt caaagaagcc aagcagctgc tgaaagtgca gaaggcttac caccagctgg atcagagctt catcgatact tatatcgacc tgctggagac tcggagaacc tactatgagg gaccaggaga agggagcccc ttcggatgga aagacatcaa ggaatggtac gagatgctga tgggacattg cacctatttt ccagaagagc tgagaagcgt caagtacgct tataacgcag atctgtacaa cgccctgaat gacctgaaca acctggtcat caccagggat gaaaacgaga aactggaata ctatgagaag ttccagatca tcgaaaacgt gtttaagcag aagaaaaagc ctacactgaa acagattgct aaggagatcc tcgtcaacga agaggacatc aagggctacc gggtgacaag cactggaaaa ccagagttca ccaatctgaa agtgtatcac gatattaagg acatcacagc acggaaagaa  atcattgaga acgccgaact gctggatcag attgctaaga tcctgactat ctaccagagc tccgaggaca tccaggaaga gctgactaac ctgaacagcg agctgaccca ggaagagatc gaacagatta gtaatctgaa ggggtacacc ggaacacaca acctgtccct gaaagctatc aatctgattc tggatgagct gtggcataca aacgacaatc agattgcaat ctttaaccgg ctgaagctgg tcccaaaaaa ggtggacctg agtcagcaga aagagatccc aaccacactg gtggacgatt tcattctgtc acccgtggtc aagcggagct tcatccagag catcaaagtg atcaacgcca tcatcaagaa gtacggcctg cccaatgata tcattatcga gctggctagg gagaagaaca gcaaggacgc acagaagatg atcaatgaga tgcagaaacg aaaccggcag accaatgaac gcattgaaga gattatccga actaccggga aagagaacgc aaagtacctg attgaaaaaa tcaagctgca cgatatgcag gagggaaagt gtctgtattc tctggaggcc atccccctgg aggacctgct gaacaatcca ttcaactacg aggtcgatca tattatcccc agaagcgtgt ccttcgacaa ttcctttaac aacaaggtgc tggtcaagca ggaagagaac tctaaaaagg gcaataggac tcctttccag tacctgtcta gttcagattc caagatctct tacgaaacct ttaaaaagca cattctgaat ctggccaaag gaaagggccg catcagcaag accaaaaagg agtacctgct ggaagagcgg gacatcaaca gattctccgt ccagaaggat tttattaacc ggaatctggt ggacacaaga tacgctacto gcggcctgat gaatctgctg cgatcctatt tccgggtgaa caatctggat gtgaaagtca agtccatcaa cggcgggttc acatcttttc tgaggcgcaa atggaagttt aaaaaggagc gcaacaaagg gtacaagcac catgccgaag atgctctgat tatcgcaaat gccgacttca tctttaagga gtggaaaaag ctggacaaag ccaagaaagt gatggagaac cagatgttcg aagagaagca ggccgaatct atgcccgaaa tcgagacaga acaggagtac aaggagattt tcatcactcc tcaccagatc aagcatatca aggatttcaa ggactacaag tactctcacc gggtggataa aaagcccaac agagagctga tcaatgacac cctgtatagt acaagaaaag acgataaggg gaataccctg attgtgaaca atctgaacgg actgtacgac aaagataatg acaagctgaa aaagctgatc aacaaaagtc ccgagaagct gctgatgtac caccatgatc ctcagacata tcagaaactg aagctgatta tggagcagta cggcgacgag aagaacccac tgtataagta ctatgaagag actgggaact acctgaccaa gtatagcaaa aaggataatg gccccgtgat caagaagatc aagtactatg ggaacaagct gaatgcccat ctggacatca cagacgatta ccctaacagt cgcaacaagg tggtcaagct gtcactgaag ccatacagat tcgatgtcta tctggacaac ggcgtgtata aatttgtgac tgtcaagaat ctggatgtca tcaaaaagga gaactactat gaagtgaata gcaagtgcta cgaagaggct aaaaagctga aaaagattag caaccaggca gagttcatcg cctcctttta caacaacgac ctgattaaga tcaatggcga actgtatagg gtcatcgggg tgaacaatga tctgctgaac cgcattgaag tgaatatgat tgacatcact taccgagagt atctggaaaa catgaatgat aagcgccccc ctcgaattat caaaacaatt gcctctaaga ctcagagtat caaaaagtac tcaaccgaca ttctgggaaa cctgtatgag gtgaagagca aaaagcaccc tcagattatc aaaaagggc   SEQ ID NO: 134 Polynucleotide sequence of N580A mutant of Staphylococcus aureus Cas9 atgaaaagga actacattct ggggctggac atcgggatta caagcgtggg gtatgggatt attgactatg aaacaaggga cgtgatcgac gcaggcgtca gactgttcaa ggaggccaac gtggaaaaca atgagggacg gagaagcaag aggggagcca ggcgcctgaa acgacggaga aggcacagaa tccagagggt gaagaaactg ctgttcgatt acaacctgct gaccgaccat tctgagctga gtggaattaa tccttatgaa gccagggtga aaggcctgag tcagaagctg tcagaggaag agttttccgc agctctgctg cacctggcta agcgccgagg agtgcataac gtcaatgagg tggaagagga caccggcaac gagctgtcta caaaggaaca gatctcacgc aatagcaaag ctctggaaga gaagtatgtc gcagagctgc agctggaacg gctgaagaaa gatggcgagg tgagagggtc aattaatagg ttcaagacaa gcgactacgt caaagaagcc aagcagctgc tgaaagtgca gaaggcttac caccagctgg atcagagctt catcgatact tatatcgacc tgctggagac tcggagaacc tactatgagg gaccaggaga agggagcccc ttcggatgga aagacatcaa ggaatggtac gagatgctga tgggacattg cacctatttt ccagaagagc tgagaagcgt caagtacgct tataacgcag atctgtacaa cgccctgaat gacctgaaca acctggtcat caccagggat gaaaacgaga aactggaata ctatgagaag ttccagatca tcgaaaacgt gtttaagcag aagaaaaagc ctacactgaa acagattgct aaggagatcc tggtcaacga agaggacatc aagggctacc gggtgacaag cactggaaaa ccagagttca ccaatctgaa agtgtatcac gatattaagg acatcacagc acggaaagaa atcattgaga acgccgaact gctggatcag attgctaaga tcctgactat ctaccagagc tccgaggaca tccaggaaga gctgactaac ctgaacagcg agctgaccca ggaagagatc gaacagatta gtaatctgaa ggggtacacc ggaacacaca acctgtccct gaaagctatc aatctgattc tggatgagct gtggcataca aacgacaatc agattgcaat ctttaaccgg ctgaagctgg tcccaaaaaa ggtggacctg agtcagcaga aagagatccc aaccacactg gtggacgatt tcattctgtc acccgtggtc aagcggagct tcatccagag catcaaagtg atcaacgcca tcatcaagaa gtacggcctg cccaatgata tcattatcga gctggctagg gagaagaaca gcaaggacgc acagaagatg atcaatgaga tgcagaaacg aaaccggcag accaatgaac gcattgaaga gattatccga actaccggga aagagaacgc aaagtacctg attgaaaaaa tcaagctgca cgatatgcag gagggaaagt gtctgtattc tctggaggcc atccccctgg aggacctgct gaacaatcca ttcaactacg aggtcgatca tattatcccc agaagcgtgt ccttcgacaa ttcctttaac aacaaggtgc tggtcaagca ggaagaggcc tctaaaaagg gcaataggac tcctttccag tacctgtcta gttcagattc caagatctct tacgaaacct ttaaaaagca cattctgaat ctggccaaag gaaagggccg catcagcaag accaaaaagg agtacctgct ggaagagcgg gacatcaaca gattctccgt ccagaaggat tttattaacc ggaatctggt ggacacaaga tacgctactc gcggcctgat gaatctgctg cgatcctatt tccgggtgaa caatctggat gtgaaagtca agtccatcaa cggcgggttc acatcttttc tgaggcgcaa atggaagttt aaaaaggagc gcaacaaagg gtacaagcac catgccgaag atgctctgat tatcgcaaat gccgacttca tctttaagga gtggaaaaag ctggacaaag ccaagaaagt gatggagaac cagatgttcg aagagaagca ggccgaatct atgcccgaaa tcgagacaga acaggagtac aaggagattt tcatcactcc tcaccagatc aagcatatca aggatttcaa ggactacaag tactctcacc gggtggataa aaagcccaac agagagctga tcaatgacac cctgtatagt acaagaaaag acgataaggg gaataccctg attgtgaaca atctgaacgg actgtacgac aaagataatg acaagctgaa aaagctgatc aacaaaagtc ccgagaagct gctgatgtac caccatgatc ctcagacata tcagaaactg aagctgatta tggagcagta cggcgacgag aagaacccac tgtataagta ctatgaagag actgggaact acctgaccaa gtatagcaaa aaggataatg gccccgtgat caagaagatc aagtactatg ggaacaagct gaatgcccat ctggacatca cagacgatta ccctaacagt cgcaacaagg tggtcaagct gtcactgaag ccatacagat tcgatgtcta tctggacaac ggcgtgtata aatttgtgac tgtcaagaat ctggatgtca tcaaaaagga gaactactat gaagtgaata gcaagtgcta cgaagaggct aaaaagctga aaaagattag caaccaggca gagttcatcg cctcctttta caacaacgac ctgattaaga tcaatggcga actgtatagg gtcatcgggg tgaacaatga tctgctgaac cgcattgaag tgaatatgat tgacatcact taccgagagt atctggaaaa catgaatgat aagcgccccc ctcgaattat caaaacaatt gcctctaaga ctcagagtat caaaaagtac tcaaccgaca ttctgggaaa cctgtatgag gtgaagagca aaaagcaccc tcagattatc aaaaagggc SEQ ID NO: 135 GS linker (Gly-Gly-Gly-Gly-Ser)_(n), wherein _(n) is an integer between 0 and 10 SEQ ID NO: 136 Gly-Gly-Gly-Gly-Gly SEQ ID NO: 137 Gly-Gly-Ala-Gly-Gly SEQ ID NO: 138 Gly-Gly-Gly-Gly-Ser-Ser-Ser SEQ ID NO: 139 Gly-Gly-Gly-Gly-Ala-Ala-Ala SEQ ID NO: 140 Human p300 (with L553M mutation) protein MAENVVEPGPPSAKRPKLSSPALSASASDGTDFGSLFDLEHDLPDELINSTELGLTNGGDINQLQTSL GMVQDAASKHKQLSELLRSGSSPNLNMGVGGPGQVMASQAQQSSPGLGLINSMVKSPMTQAGLTSPNM GMGTSGPNQGPTQSTGMMNSPVNQPAMGMNTGMNAGMNPGMLAAGNGQGIMPNQVMNGSIGAGRGRQN MQYPNPGMGSAGNLLTEPLQQGSPQMGGQTGLRGPQPLKMGMMNNPNPYGSPYTQNPGQQIGASGLGL QIQTKTVLSNNLSPFAMDKKAVPGGGMPNMGQQPAPQVQQPGLVTPVAQGMGSGAHTADPEKRKLIQQ QLVLLLHAHKCORREQANGEVRQCNLPHCRTMKNVLNHMTHCQSGKSCQVAHCASSRQIISHWKNCTR HDCPVCLPLKNAGDKRNQQPILTGAPVGLGNPSSLGVGQQSAPNLSTVSQIDPSSIERAYAALGLPYQ VNQMPTOPQVQAKNQQNQQPGQSPQGMRPMSNMSASPMGVNGGVGVQTPSLLSDSMLHSAINSQNPMM SENASVPSMGPMPTAAQPSTTGIRKQWHEDITQDLRNHLVHKLVQAIFPTPDPAALKDRRMENLVAYA RKVEGDMYESANNRAEYYHLLAEKIYKIQKELEEKRRTRLQKQNMLPNAAGMVPVSMNPGPNMGQPQP GMTSNGPLPDPSMIRGSVPNQMMPRITPQSGLNQFGQMSMAQPPIVPRQTPPLQHHGQLAQPGALNPP MGYGPRMQQPSNOGQFLPQTQFPSQGMNVTNIPLAPSSGQAPVSQAQMSSSSCPVNSPIMPPGSQGSH IHCPQLPQPALHQNSPSPVPSRTPTPHHTPPSTGAQQPPATTIPAPVPTPPAMPPGPQSQALHPPPRQ TPTPPTTQLPQQVQPSLPAAPSADQPQQQPRSQQSTAASVPTPTAPLLPPQPATPLSQPAVSIEGQVS NPPSTSSTEVNSQAIAEKQPSQEVKMEAKMEVDQPEPADTQPEDISESKVEDCKMESTETEERSTELK TEIKEEEDQPSTSATQSSPAPGQSKKKIFKPEELRQALMPTLEALYRQDPESLPFRQPVDPQLLGIPD YFDIVKSPMDLSTIKRKLDTGQYQEPWQYVDDIWLMFNNAWLYNRKTSRVYKYCSKLSEVFEQEIDPV MQSLGYCCGRKLEFSPQTLCCYGKQLCTIPRDATYYSYQNRYHFCEKCFNEIQGESVSLGDDPSQPQT TTNKEQFSKRKNDTLDPELFVECTECGRKMHQICVLHHEIIWPAGFVCDGCLKKSARTRKENKFSAKR LPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKAL FAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRPKCLRTAVYHEILTGYLEYVKKL GYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLT SAKELPYFEGDFWPNVLEESIKELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLS RGNKKKPGMPNVSNDLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLT LARDKHLEFSSLRRAQWSTMCMLVELHTQSQDRFVYTCNECKHHVETRWHCTVCEDYDLCITCYNTKN HDHKMEKLGLGLDDESNNQQAAATQSPGDSRRLSIQRCIQSLVHACQCRNANCSLPSCQKMKRVVQHT KGCKRKTNGGCPICKQLIALCCYHAKHCQENKCPVPFCLNIKQKLRQQQLQHRLQQAQMLRRRMASMQ RTGVVGQQQGLPSPTPATPTTPTGQQPTTPQTPQPTSQPQPTPPNSMPPYLPRTQAAGPVSQGKAAGQ VTPPTPPQTAQPPLPGPPPAAVEMAMQIQRAAETQRQMAHVQIFQRPIQHQMPPMTPMAPMGMNPPPM TRGPSGHLEPGMGPTGMQQQPPWSQGGLPQPQQLQSGMPRPAMMSVAQHGQPLNMAPQPGLGQVGISP LKPGTVSQQALQNLLRTLRSPSSPLQQQQVLSILHANPQLLAAFIKQRAAKYANSNPQPIPGQPGMPQ GQPGLQPPTMPGQQGVHSNPAMQNMNPMQAGVQRAGLPQQQPQQQLQPPMGGMSPQAQQMNMNHNTMP SQFRDILRRQQMMQQQQQQGAGPGIGPGMANHNQFQQPQGVGYPPQQQQRMQHHMQQMQQGNMGQIGQ LPQALGAEAGASLQAYQQRLLQQQMGSPVQPNPMSPQQHMLPNQAQSPHLQGQQIPNSLSNQVRSPQP VPSPRPQSOPPHSSPSPRMQPQPSPHHVSPQTSSPHPGLVAAQANPMEQGHFASPDQNSMLSQLASNP GMANLHGASATDLGLSTDNSDLNSNLSQSTLDIH SEQ ID NO: 141 Human p300 Core Effector protein (aa 1048-1664 of SEQ ID NO: 140) IFKPEELRQALMPTLEALYRQDPESLPFRQPVDPQLLGIPDYFDIVKSPMDLSTIKRKLDTGQYQEPW QYVDDIWLMFNNAWLYNRKTSRVYKYCSKLSEVFEQEIDPVMQSLGYCCGRKLEFSPQTLCCYGKQLC TIPRDATYYSYQNRYHFCEKCFNEIQGESVSLGDDPSQPQTTINKEQFSKRKNDTLDPELFVECTECG RKMHQICVLHHEIIWPAGFVCDGCLKKSARTRKENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESG EVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPP PNQRRVYISYLDSVHFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQ KIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQE EEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKH KEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKHLEFSSLRRAQWSTMCMLVELH TQSQD SEQ ID NO: 142 VP64-dCas9-VP64 protein RADALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMVNPKKKRKVGRGMDKKY SIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYT RRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKK LVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAK AILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDN LLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPE KYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQ IHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEV VDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIV DLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILE DIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKS DGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHTANLAGSPAIKKGILQTVKVVDELVKVMGR HKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRD MYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNA KLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVIT LKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKS EQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVN IVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVK ELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALP SKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKH RDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTTDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGDSRADPKKKRKVASRADALDDFDLDMLGSDALDDFDLDMLGSDALDDEDLDMLGSDALDDFDLDML I SEQ ID NO: 143 VP64-dCas9-VP64 DNA cgggctgacgcattggacgattttgatctggatatgctgggaagtgacgccctcgatgattttgacct tgacatgcttggttcggatgcccttgatgactttgacctcgacatgctcggcagtgacgcccttgatg atttcgacctggacatggttaaccccaagaagaagaggaaggtgggccgcggaatggacaagaagtac tccattgggctcgccatcggcacaaacagcgtcggctgggccgtcattacggacgagtacaaggtgcc gagcaaaaaattcaaagttctgggcaataccgatcgccacagcataaagaagaacctcattggcgccc tcctgttcgactccggggaaaccgccgaagccacgcggctcaaaagaacagcacggcgcagatatacc cgcagaaagaatcggatctgctacctgcaggagatctttagtaatgagatggctaaggtggatgactc tttcttccataggctggaggagtcctttttggtggaggaggataaaaagcacgagcgccacccaatct ttggcaatatcgtggacgaggtggcgtaccatgaaaagtacccaaccatatatcatctgaggaagaag cttgtagacagtactgataaggctgacttgcggttgatctatctcgcgctggcgcatatgatcaaatt tcggggacacttcctcatcgagggggacctgaacccagacaacagcgatgtcgacaaactctttatcc aactggttcagacttacaatcagcttttcgaagagaacccgatcaacgcatccggagttgacgccaaa gcaatcctgagcgctaggctgtccaaatcccggcggctcgaaaacctcatcgcacagctccctgggga gaagaagaacggcctgtttggtaatcttatcgccctgtcactcgggctgacccccaactttaaatcta acttcgacctggccgaagatgccaagcttcaactgagcaaagacacctacgatgatgatctcgacaat ctgctggcccagatcggcgaccagtacgcagacctttttttggcggcaaagaacctgtcagacgccat tctgctgagtgatattctgcgagtgaacacggagatcaccaaagctccgctgagcgctagtatgatca agcgctatgatgagcaccaccaagacttgactttgctgaaggcccttgtcagacagcaactgcctgag aagtacaaggaaattttcttcgatcagtctaaaaatggctacgccggatacattgacggcggagcaag ccaggaggaattttacaaatttattaagcccatcttggaaaaaatggacggcaccgaggagctgctgg attcacctgggcgaactgcacgctatcctcaggcggcaagaggatttctacccctttttgaaagataa cagggaaaagattgagaaaatcctcacatttcggataccctactatgtaggccccctcgcccggggaa attccagattcgcgtggatgactcgcaaatcagaagagaccatcactccctggaacttcgaggaagtc gtggataagggggcctctgcccagtccttcatcgaaaggatgactaactttgataaaaatctgcctaa cgaaaaggtgcttcctaaacactctctgctgtacgagtacttcacagtttataacgagctcaccaagg tcaaatacgtcacagaagggatgagaaagccagcattcctgtctggagagcagaagaaagctatcgtg gacctcctcttcaagacgaaccggaaagttaccgtgaaacagctcaaagaagactatttcaaaaagat tgaatgtttcgactctgttgaaatcagcggagtggaggatcgcttcaacgcatccctgggaacgtatc acgatctcctgaaaatcattaaagacaaggacttcctggacaatgaggagaacgaggacattcttgag gacattgtcctcacccttacgttgtttgaagatagggagatgattgaagaacgcttgaaaacttacgc tcatctcttcgacgacaaagtcatgaaacagctcaagaggcgccgatatacaggatgggggcggctgt caagaaaactgatcaatgggatccgagacaagcagagtggaaagacaatcctggattttcttaagtcc gatggatttgccaaccggaacttcatgcagttgatccatgatgactctctcacctttaaggaggacat ccagaaagcacaagtttctggccagggggacagtcttcacgagcacatcgctaatcttgcaggtagcc cagctatcaaaaagggaatactgcagaccgttaaggtcgtggatgaactcgtcaaagtaatgggaagg cataagcccgagaatatcgttatcgagatggcccgagagaaccaaactacccagaagggacagaagaa cagtagggaaaggatgaagaggattgaagagggtataaaagaactggggtcccaaatccttaaggaac acccagttgaaaacacccagcttcagaatgagaagctctacctgtactacctgcagaacggcagggac atgtacgtggatcaggaactggacatcaatcggctctccgactacgacgtggatgccatcgtgcccca gtcttttctcaaagatgattctattgataataaagtgttgacaagatccgataaaaatagagggaaga gtgataacgtcccctcagaagaagttgtcaagaaaatgaaaaattattggcggcagctgctgaacgcc aaactgatcacacaacggaagttcgataatctgactaaggctgaacgaggtggcctgtctgagttgga taaagccggcttcatcaaaaggcagcttgttgagacacgccagatcaccaagcacgtggcccaaattc tcgattcacgcatgaacaccaagtacgatgaaaatgacaaactgattcgagaggtgaaagttattact ctgaagtctaagctggtctcagatttcagaaaggactttcagttttataaggtgagagagatcaacaa ttaccaccatgcgcatgatgcctacctgaatgcagtggtaggcactgcacttatcaaaaaatatccca agcttgaatctgaatttgtttacggagactataaagtgtacgatgttaggaaaatgatcgcaaagtct gagcaggaaataggcaaggccaccgctaagtacttcttttacagcaatattatgaattttttcaagac cgagattacactggccaatggagagattcggaagcgaccacttatcgaaacaaacggagaaacaggag aaatcgtgtgggacaagggtagggatttcgcgacagtccggaaggtcctgtccatgccgcaggtgaac atcgttaaaaagaccgaagtacagaccggaggcttctccaaggaaagtatcctcccgaaaaggaacag cgacaagctgatcgcacgcaaaaaagattgggaccccaagaaatacggcggattcgattctcctacag tcgcttacagtgtactggttgtggccaaagtggagaaagggaagtctaaaaaactcaaaagcgtcaag gaactgctgggcatcacaatcatggagcgatcaagcttcgaaaaaaaccccatcgactttctcgaggc gaaaggatataaagaggtcaaaaaagacctcatcattaagcttcccaagtactctctctttgagcttg aaaacggccggaaacgaatgctcgctagtgcgggcgagctgcagaaaggtaacgagctggcactgccc tctaaatacgttaatttcttgtatctggccagccactatgaaaagctcaaagggtctcccgaagataa tgagcagaagcagctgttcgtggaacaacacaaacactaccttgatgagatcatcgagcaaataagcg aattctccaaaagagtgatcctcgccgacgctaacctcgataaggtgctttctgcttacaataagcac agggataagcccatcagggagcaggcagaaaacattatccacttgtttactctgaccaacttgggcgc gcctgcagccttcaagtacttcgacaccaccatagacagaaagcggtacacctctacaaaggaggtcc tggacgccacactgattcatcagtcaattacggggctctatgaaacaagaatcgacctctctcagctc ggtggagacagcagggctgaccccaagaagaagaggaaggtggctagccgcgccgacgcgctggacga tttcgatctcgacatgctgggttctgatgccctcgatgactttgacctggatatgttgggaagcgacg cattggatgactttgatctggacatgctcggctccgatgctctggacgatttcgatctcgatatgtta atc SEQ ID NO: 144 Protein sequence for VPH DALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSLPSASVEFEGSGGPSG QISNQALALAPSSAPVLAQTMVPSSAMVPLAQPPAPAPVLTPGPPQSLSAPVPKSTQAGEGTLSEALL HLQFDADEDLGALLGNSTDPGVFTDLASVDNSEFQQLLNQGVSMSHSTAEPMLMEYPEAITRLVTGSQ RPPDPAPTPLGTSGLPNGLSGDEDFSSIADMDFSALLSQISSSGQGGGGSGFSVDTSALLDLFSPSVT VPDKSLPDLDSSLASIQELLSPQEPPRPPEAENSSPDSGKQLVHYTAQPLFLLDPGSVDTGSNDLPVL FELGEGSYFSEGDGFAEDPTISLLTGSEPPKAKDPTVS SEQ ID NO: 145 DNA sequence for VPH gatgctttagacgattttgacttagatatgcttggttcagacgcgttagacgacttcgacctagacat gttaggctcagatgcattggacgacttcgatttagatatgttgggctccgatgccctagatgactttg atctagatatgctagggtcactacccagcgccagcgtcgagttcgaaggcagcggcgggccttcaggg cagatcagcaaccaggccctggctctggcccctagctccgctccagtgctggcccagactatggtgcc ctctagtgctatggtgcctctggcccagccacctgctccagcccctgtgctgaccccaggaccacccc agtcactgagcgccccagtgcccaagtctacacaggccggcgaggggactctgagtgaagctctgctg cacctgcagttcgacgctgatgaggacctgggagctctgctggggaacagcaccgatcccggagtgtt cacagatctggcctccgtggacaactctgagtttcagcagctgctgaatcagggcgtgtccatgtctc atagtacagccgaaccaatgctgatggagtaccccgaagccattacccggctggtgaccggcagccag cggccccccgaccccgctccaactcccctgggaaccagcggcctgcctaatgggctgtccggagatga agacttctcaagcatcgctgatatggactttagtgccctgctgtcacagatttcctctagtgggcagg gaggaggtggaagcggcttcagcgtggacaccagtgccctgctggacctgttcagcccctcggtgacc gtgcccgacatgagcctgcctgaccttgacagcagcctggccagtatccaagagctcctgtctcccca ggagccccccaggcctcccgaggcagagaacagcagcccggattcagggaagcagctggtgcactaca cagcgcagccgctgttcctgctggaccccggctccgtggacaccgggagcaacgacctgccggtgctg tttgagctgggagagggctcctacttctccgaaggggacggcttcgccgaggaccccaccatctccct gcf.gacaggctcggagcctcccaaagccaaggaccccactgtctcc SEQ ID NO: 146 Protein sequence for VPR DALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSDALDDFDLDMLGSPKKKRKVGSQYLPDTD DRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYD EFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVLAPGPPQAVAPPAPKPT QAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQGIPVAPHTTEPMLMEYP EAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSTADMDFSALLSQISSGSGSGSRDSREGMF LPKPEAGSAISDVFEGREVCQPKRIRPFHPPGSPWANRPLPASLAPTPTGPVHEPVGSLTPAPVPQPL DPAPAVTPEASHLLEDPDEETSQAVKALREMADTVIPQKEEAAICGQMDLSHPPPRGHLDELTTTLES MTEDLNLDSPLTPELNEILDTELNDECLLHAMHISTGLSIFDTSLF SEQ ID NO: 147 DNA sequence for VPR gatgctttagacgattttgacttagatatgcttggttcagacgcgttagacgacttcgacctagacat gttaggctcagatgcattggacgacttcgatttagatatgttgggctccgatgccctagatgactttg atctagatatgctaggtagtcccaaaaagaagaggaaagtgggatcccagtatctgcccgacacagat gatagacaccgaatcgaagagaaacgcaagcgaacgtatgaaaccttcaaatcgatcatgaagaaatc gcccttctcgggtccgaccgatcccaggcccccaccgagaaggattgcggtcccgtcccgctcgtcgg ccagcgtgccgaagcctgcgccgcagccctaccccttcacgtcgagcctgagcacaatcaattatgac gagttcccgacgatggtgttcccctcgggacaaatctcacaagcctcggcgctcgcaccagcgcctcc ccaagtccttccgcaagcgcctgccccagcgcctgcaccggcaatggtgtccgccctcgcacaggccc ctgcgcccgtccccgtgctcgcgcctggaccgccccaggcggtcgctccaccggctccgaagccgacg caggccggagagggaacactctccgaagcacttcttcaactccagtttgatgacgaggatcttggagc actccttggaaactcgacagaccctgcggtgtttaccgacctcgcgtcagtagataactccgaatttc agcagcctttgaaccagggtatcccggtcgcgccacatacaacggagcccatgttgatggaatacccc gaagcaatcacgagacttgtgacgggagcgcagcggcctcccgatcccgcacccgcacctttgggggc acctggcctccctaacggacttttgagcggcgacgaggatttctcctccatcgccgatatggatttct cagccttgctgtcacagatttccagcggctctggcagcggcagccgggattccagggaagggatgttt ttgccgaagcctgaggccggctccgctattagtgacgtgtttgagggccgcgaggtgtgccagccaaa acgaatccggccatttcatcctccaggaagtccatgggccaaccgcccactccccgccagcctcgcac caacaccaaccggtccagtacatgagccagtcgggtcactgaccccggcaccagtccctcagccactg gatccagcgcccgcagtgactcccgaggccagtcacctgttggaggatcccgatgaagagacgagcca ggctgtcaaagcccttcgggagatggccgatactgtgattccccagaaggaagaggctgcaatctgtg gccaaatggacctttcccatccgcccccaaggggccatctggatgagctgacaaccacacttgagtcc atgaccgaggatctgaacctggactcacccctgaccccggaattgaacgagattctggataccttcct gaacgacgagtgcctcttgcatgccatgcatatcagcacaggactgtccatcttcgacacatctctgt tt SEQ ID NO: 148 Polynucleotide sequence encoding Streptccoccus pyogenes dCas9-KRAB atggactacaaagaccatgacggtgattataaagatcatgacatcgattacaaggatgacgatgacaa gatggcccccaagaagaagaggaaggtgggccgcggaatggacaagaagtactccattgggctcgcca tcggcacaaacagcgtcggctgggccgtcattacggacgagtacaaggtgccgagcaaaaaattcaaa gttctgggcaataccgatcgccacagcataaagaagaacctcattggcgccctcctgttcgactccgg ggaaaccgccgaagccacgcggctcaaaagaacagcacggcgcagatatacccgcagaaagaatcgga tctgctacctgcaggagatctttagtaatgagatggctaaggtggatgactctttcttccataggctg gaggagtcctttttggtggaggaggataaaaagcacgagcgccacccaatctttggcaatatcgtgga cgaggtggcgtaccatgaaaagtacccaaccatatatcatctgaggaagaagcttgtagacagtactg ataaggctgacttgcggttgatctatctcgcgctggcgcatatgatcaaatttcggggacacttcctc atcgagggggacctgaacccagacaacagcgatgtcgacaaactctttatccaactggttcagactta caatcagcttttcgaagagaacccgatcaacgcatccggagttgacgccaaagcaatcctgagcgcta ggctgtccaaatcccggcggctcgaaaacctcatcgcacagctccctggggagaagaagaacggcctg tttggtaatcttatcgccctgtcactcgggctgacccccaactttaaatctaacttcgacctggccga agatgccaagcttcaactgagcaaagacacctacgatgatgatctcgacaatctgctggcccagatcg gcgaccagtacgcagacctttttttggcggcaaagaacctgtcagacgccattctgctgagtgatatt ctgcgagtgaacacggagatcaccaaagctccgctgagcgctagtatgatcaagcgctatgatgagca ccaccaagacttgactttgctgaaggcccttgtcagacagcaactgcctgagaagtacaaggaaattt tcttcgatcagtctaaaaatggctacgccggatacattgacggcggagcaagccaggaggaattttac aaatttattaagcccatcttggaaaaaatggacggcaccgaggagctgctggtaaagcttaacagaga agatctgttgcgcaaacagcgcactttcgacaatggaagcatcccccaccagattcacctgggcgaac tgcacgctatcctcaggcggcaagaggatttctacccctttttgaaagataacagggaaaagattgag aaaatcctcacatttaggataccctactatgtaggccccctcgcccggggaaattccagattcgcgtg gatgactcgcaaatcagaagagaccatcactccctggaacttcgaggaagtcgtggataagggggcct ctgcccagtccttcatcgaaaggatgactaactttgataaaaatctgcctaacgaaaaggtgcttcct aaacactctctgctgtacgagtacttcacagtttataacgagctcaccaaggtcaaatacgtcacaga agggatgagaaagccagcattcctgtctggagagcagaagaaagctatcgtggacctcctcttcaaga cgaaccggaaagttaccgtgaaacagctcaaagaagactatttcaaaaagattgaatgtttcgactct gttgaaatcagcggagtggaggatcgcttcaacgcatccctgggaacgtatcacgatctcctgaaaat cattaaagacaaggacttcctggacaatgaggagaacgaggacattcttgaggacattgtcctcaccc ttacgttgtttgaagatagggagatgattgaagaacgcttgaaaacttacgctcatctcttcgacgac aaagtcatgaaacagctcaagaggcgccgatatacaggatgggggcggctgtcaagaaaactgatcaa tgggatccgagacaagcagagtggaaagacaatcctggattttcttaagtccgatggatttgccaacc ggaacttcatgcagttgatccatgatgactctctcacctttaaggaggacatccagaaagcacaagtt tctggccagggggacagtcttcacgagcacatcgctaatcttgcaggtagcccagctatcaaaaaggg aatactgcagaccgttaaggtcgtggatgaactcgtcaaagtaatgggaaggcataagcccgagaata tcgttatcgagatggcccgagagaaccaaactacccagaagggacagaagaacagtagggaaaggatg aagaggattgaagagggtataaaagaactggggtcccaaatccttaaggaacacccagttgaaaacac ccagcttcagaatgagaagctctacctgtactacctgcagaacggcagggacatgtacgtggatcagg aactggacatcaatcggctctccgactacgacgtggatgccatcgtgccccagtcttttctcaaagat gattctattgataataaagtgttgacaagatccgataaaaatagagggaagagtgataacgtcccctc agaagaagttgtcaagaaaatgaaaaattattggcggcagctgctgaacgccaaactgatcacacaac ggaagttcgataatctgactaaggctgaacgaggtggcctgtctgagttggataaagccggcttcatc aaaaggcagcttgttgagacacgccagatcaccaagcacgtggcccaaattctcgattcacgcatgaa caccaagtacgatgaaaatgacaaactgattcgagaggtgaaagttattactctgaagtctaagctgg tctcagatttcagaaaggactttcagttttataaggtgagagagatcaacaattaccaccatgcgcat gatgcctacctgaatgcagtggtaggcactgcacttatcaaaaaatatcccaagcttgaatctgaatt tgtttacggagactataaagtgtacgatgttaggaaaatgatcgcaaagtctgagcaggaaataggca aggccaccgctaagtacttcttttacagcaatattatgaattttttcaagaccgagattacactggcc aatggagagattcggaagcgaccacttatcgaaacaaacggagaaacaggagaaatcgtgtgggacaa gggtagggatttcgcgacagtccggaaggtcctgtccatgccgcaggtgaacatcgttaaaaagaccg aagtacagaccggaggcttctccaaggaaagtatcctcccgaaaaggaacagcgacaagctgatcgca cgcaaaaaagattgggaccccaagaaatacggcggattcgattctcctacagtcgcttacagtgtact ggttgtggccaaagtggagaaagggaagtctaaaaaactcaaaagcgtcaaggaactgctgggcatca caatcatggagcgatcaagcttcgaaaaaaaccccatcgactttctcgaggcgaaaggatataaagag gtcaaaaaagacctcatcattaagcttcccaagtactctctctttgagcttgaaaacggccggaaacg aatgctcgctagtgcgggcgagctgcagaaaggtaacgagctggcactgccctctaaatacgttaatt tcttgtatctggccagccactatgaaaagctcaaagggtctcccgaagataatgagcagaagcagctg ttcgtggaacaacacaaacactaccttgatgagatcatcgagcaaataagcgaattctccaaaagagt gatcctcgccgacgctaacctcgataaggtgctttctgcttacaataagcacagggataagcccatca gggagcaggcagaaaacattatccacttgtttactctgaccaacttgggcgcgcctgcagccttcaag tacttcgacaccaccatagacagaaagcggtacacctctacaaaggaggtcctggacgccacactgat tcatcagtcaattacggggctctatgaaacaagaatcgacctctctcagctcggtggagacagcaggg ctgaccccaagaagaagaggaaggtggctagcgatgctaagtcactgactgcctggtcccggacactg gtgaccttcaaggatgtgtttgtggacttcaccagggaggagtggaagctgctggacactgctcagca gatcctgtacagaaatgtgatgctggagaactataagaacctggtttccttgggttatcagcttacta agccagatgtgatcctccggttggagaagggagaagagccctggctggtggagagagaaattcaccaa gagacccatcctgattcagagactgcatttgaaatcaaatcatcagttccgaaaaagaaacgcaaagt ttga SEQ ID NO: 149 Polypeptide sequence of Streptccoccus pyogenes dCas9-KRAB protein MDYKDHDGDYKDHDIDYKDDDDKMAPKKKRKVGRGMDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFK VLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRL EESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFL IEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGL FGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDI LRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIE KILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLP KHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDS VEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDD KVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQV SGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERM KRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKD DSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWROLLNAKLITQRKFDNLTKAERGGLSELDKAGFI KRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAH DAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLA NGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIA RKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKE VKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQL FVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFK YFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSRADPKKKRKVASDAKSLTAWSRTL VTFKDVFVDFTREEWKLLDTAQQILYRNVMLENYKNLVSLGYQLTKPDVILRLEKGEEPWLVEREIHQ ETHPDSETAFEIKSSVPKKKRKV SEQ ID NO: 150 Polynucleotide sequence of Staphylococcus aureus dCas9-KRAB protein atggccccaaagaagaagcggaaggtcggtatccacggagtcccagcagccaagcggaactacatcct gggcctggccatcggcatcaccagcgtgggctacggcatcatcgactacgagacacgggacgtgatcg atgccggcgtgcggctgttcaaagaggccaacgtggaaaacaacgagggcaggcggagcaagagaggc gccagaaggctgaagcggcggaggcggcatagaatccagagagtgaagaagctgctgttcgactacaa cctgctgaccgaccacagcgagctgagcggcatcaacccctacgaggccagagtgaagggcctgagcc agaagctgagcgaggaagagttctctgccgccctgctgcacctggccaagagaagaggcgtgcacaac gtgaacgaggtggaagaggacaccggcaacgagctgtccaccaaagagcagatcagccggaacagcaa ggccctggaagagaaatacgtggccgaactgcagctggaacggctgaagaaagacggcgaagtgcggg gcagcatcaacagattcaagaccagcgactacgtgaaagaagccaaacagctgctgaaggtgcagaag gcctaccaccagctggaccagagcttcatcgacacctacatcgacctgctggaaacccggcggaccta ctatgagggacctggcgagggcagccccttcggctggaaggacatcaaagaatggtacgagatgctga tgggccactgcacctacttccccgaggaactgcggagcgtgaagtacgcctacaacgccgacctgtac aacgccctgaacgacctgaacaatctcgtgatcaccagggacgagaacgagaagctggaatattacga gaagttccagatcatcgagaacgtgttcaagcagaagaagaagcccaccctgaagcagatcgccaaag aaatcctcgtgaacgaagaggatattaagggctacagagtgaccagcaccggcaagcccgagttcacc aacctgaaggtgtaccacgacatcaaggacattaccgcccggaaagagattattgagaacgccgagct gctggatcagattgccaagatcctgaccatctaccagagcagcgaggacatccaggaagaactgacca atctgaactccgagctgacccaggaagagatcgagcagatctctaatctgaagggctataccggcacc cacaacctgagcctgaaggccatcaacctgatcctggacgagctgtggcacaccaacgacaaccagat cgctatcttcaaccggctgaagctggtgcccaagaaggtggacctgtcccagcagaaagagatcccca ccaccctggtggacgacttcatcctgagccccgtcgtgaagagaagcttcatccagagcatcaaagtg atcaacgccatcatcaagaagtacggcctgcccaacgacatcattatcgagctggcccgcgagaagaa ctccaaggacgcccagaaaatgatcaacgagatgcagaagcggaaccggcagaccaacgagcggatcg aggaaatcatccggaccaccggcaaagagaacgccaagtacctgatcgagaagatcaagctgcacgac atgcaggaaggcaagtgcctgtacagcctggaagccatccctctggaagatctgctgaacaacccctt caactatgaggtggaccacatcatccccagaagcgtgtccttcgacaacagcttcaacaacaaggtgc tcgtgaagcaggaagaagccagcaagaagggcaaccggaccccattccagtacctgagcagcagcgac agcaagatcagctacgaaaccttcaagaagcacatcctgaatctggccaagggcaagggcagaatcag caagaccaagaaagagtatctgctggaagaacgggacatcaacaggttctccgtgcagaaagacttca tcaaccggaacctggtggataccagatacgccaccagaggcctgatgaacctgctgcggagctacttc agagtgaacaacctggacgtgaaagtgaagtccatcaatggcggcttcaccagctttctgcggcggaa gtggaagtttaagaaagagcggaacaaggggtacaagcaccacgccgaggacgccctgatcattgcca acgccgatttcatcttcaaagagtggaagaaactggacaaggccaaaaaagtgatggaaaaccagatg ttcgaggaaaagcaggccgagagcatgcccgagatcgaaaccgagcaggagtacaaagagatcttcat caccccccaccagatcaagcacattaaggacttcaaggactacaagtacagccaccgggtggacaaga agcctaatagagagctgattaacgacaccctgtactccacccggaaggacgacaagggcaacaccctg atcgtgaacaatctgaacggcctgtacgacaaggacaatgacaagctgaaaaagctgatcaacaagag ccccgaaaagctgctgatgtaccaccacgacccccagacctaccagaaactgaagctgattatggaac agtacggcgacgagaagaatcccctgtacaagtactacgaggaaaccgggaactacctgaccaagtac tccaaaaaggacaacggccccgtgatcaagaagattaagtattacggcaacaaactgaacgcccatct ggacatcaccgacgactaccccaacagcagaaacaaggtcgtgaagctgtccctgaagccctacagat tcgacgtgtacctggacaatggcgtgtacaagttcgtgaccgtgaagaatctggatgtgatcaaaaaa gaaaactactacgaagtgaatagcaagtgctatgaggaagctaagaagctgaagaagatcagcaacca ggccgagtttatcgcctccttctacaacaacgatctgatcaagatcaacggcgagctgtatagagtga tcggcgtgaacaacgacctgctgaaccggatcgaagtgaacatgatcgacatcacctaccgcgagtac ctggaaaacatgaacgacaagaggccccccaggatcattaagacaatcgcctccaagacccagagcat taagaagtacagcacagacattctgggcaacctgtatgaagtgaaatctaagaagcaccctcagatca tcaaaaagggcaaaaggccggCggccacgaaaaaggccggccaggcaaaaaagaaaaagggatccgat gctaagtcactgactgcctggtcccggacactggtgaccttcaaggatgtgtttgtggacttcaccag ggaggagtggaagctgctggacactgctcagcagatcctgtacagaaatgtgatgctggagaactata agaacctggtttccttgggttatcagcttactaagccagatgtgatcctccggttggagaagggagaa gagccctggctggtggagagagaaattcaccaagagacccatcctgattcagagactgcatttgaaat caaatcatcagttccgaaaaagaaacgcaaagtt SEQ ID NO: 151 Polypeptide sequence of Staphylococcus aureus dCas9-KRAB protein MAPKKKRKVGIHGVPAAKRNYILGLAIGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRG ARRLKRRRRHRIQRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAKRRGVHN VNEVEEDTGNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRFKTSDYVKEAKQLLKVQK AYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKEWYEMLMGHCTYFPEELRSVKYAYNADLY NALNDLNNLVITRDENEKLEYYEKFQIIENVFKQKKKPTLKQTAKEILVNEEDIKGYRVTSTGKPEFT NLKVYHDIKDITARKEIIENAELLDQIAKILTIYQSSEDIQEELTNLNSELTQEEIEQISNLKGYTGT HNLSLKAINLILDELWHTNDNQIAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQSIKV INAIIKKYGLPNDIIIELAREKNSKDAQKMINEMQKRNRQTNERIEEIIRTTGKENAKYLIEKIKLHD MQEGKCLYSLEAIPLEDLLNNPFNYEVDHIIPRSVSFDNSENNKVLVKQEEASKKGNRTPFQYLSSSD SKISYETFKKHILNLAKGKGRISKTKKEYLLEERDINRESVQKDFINRNLVDTRYATRGLMNLLRSYF RVNNLDVKVKSINGGFTSFLRRKWKFKKERNKGYKHHAEDALIIANADFIFKEWKKLDKAKKVMENQM FEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNRELINDTLYSTRKDDKGNTL IVNNLNGLYDKDNDKLKKLINKSPEKLLMYHHDPQTYQKLKLIMEQYGDEKNPLYKYYEETGNYLTKY SKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSRNKVVKLSLKPYRFDVYLDNGVYKFVTVKNLDVIKK ENYYEVNSKCYEEAKKLKKISNQAEFTASFYNNDLIKINGELYRVIGVNNDLLNRIEVNMIDITYREY LENMNDKRPPRIIKTIASKTQSIKKYSTDILGNLYEVKSKKHPQIIKKGKRPAATKKAGQAKKKKGSD AKSLTAWSRTLVTFKDVFVDFTREEWKLLDTAQQILYRNVMLENYKNLVSLGYQLTKPDVILRLEKGE EPWLVEREIHQETHPDSETAFEIKSSVPKKKRKV SEQ ID NO: 152 Polynucleotide sequence of Tet1CD CTGCCCACCTGCAGCTGTCTTGATCGAGTTATACAAAAAGACAAAGGCCCATATTATACACACCTTGG GGCAGGACCAAGTGTTGCTGCTGTCAGGGAAATCATGGAGAATAGGTATGGTCAAAAAGGAAACGCAA TAAGGATAGAAATAGTAGTGTACACCGGTAAAGAAGGGAAAAGCTCTCATGGGTGTCCAATTGCTAAG TGGGTTTTAAGAAGAAGCAGTGATGAAGAAAAAGTTCTTTGTTTGGTCCGGCAGCGTACAGGCCACCA CTGTCCAACTGCTGTGATGGTGGTGCTCATCATGGTGTGGGATGGCATCCCTCTTCCAATGGCCGACC GGCTATACACAGAGCTCACAGAGAATCTAAAGTCATACAATGGGCACCCTACCGACAGAAGATGCACC CTCAATGAAAATCGTACCTGTACATGTCAAGGAATTGATCCAGAGACTTGTGGAGCTTCATTCTCTTT TGGCTGTTCATGGAGTATGTACTTTAATGGCTGTAAGTTTGGTAGAAGCCCAAGCCCCAGAAGATTTA GAATTGATCCAAGCTCTCCCTTACATGAAAAAAACCTTGAAGATAACTTACAGAGTTTGGCTACACGA TTAGCTCCAATTTATAAGCAGTATGOTCCAGTAGCTTACCAAAATCAGGTGGAATATGAAAATGTTGC CCGAGAATGTCGGCTTGGCAGCAAGGAAGGTCGACCCTTCTCTGGGGTCACTGCTTGCCTGGACTTCT GTGCTCATCCCCACAGGGACATTCACAACATGAATAATGGAAGCACTGTGGTTTGTACCTTAACTCGA GAAGATAACCGOTCTTTGGGTGTTATTCCTCAAGATGAGCAGCTCCATGTGCTACCTCTTTATAAGCT TTCAGACACAGATGAGITTGGCTCCAAGGAAGGAATGGAAGCCAAGATCAAATCTGGGGCCATCGAGG TCCTGGCACCCCGCCGCAAAAAAAGAACGTGTTTCACTCAGCCTGTTCCCCGTTCTGGAAAGAAGAGG GCTGCGATGATGACAGAGGTTCTTGCACATAAGATAAGGGCAGTGGAAAAGAAACCTATTCCCCGAAT CAAGCGGAAGAATAACTCAACAACAACAAACAACAGTAAGCCTTCGTCACTGCCAACCTTAGGGAGTA ACACTGAGACCGTGCAACCTGAAGTAAAAAGTGAAACCGAACCCCATTTTATCTTAAAAAGTTCAGAC AACACTAAAACTTATTCGCTGATGCCATCCGCTCCTCACCCAGTGAAAGAGGCATCTCCAGGCTTCTC CTGGTCCCCGAAGACTGCTTCAGCCACACCAGCTCCACTGAAGAATGACGCAACAGCCTCATGCGGGT TTTCAGAAAGAAGCAGCACTCCCCACTGTACGATGCCTTCGGGAAGACTCAGTGGTGCCAATGCTGCA GCTGCTGATGGCCCTGGCATTTCACAGCTTGGCGAAGTGGCTCCTCTCCCCACCCTGTCTGCTCCTGT GATGGAGCCCCTCATTAATTCTGAGCCTTCCACTGGTGTGACTGAGCCGCTAACGCCTCATCAGCCAA ACCACCAGCCCTCCTTCCTCACCTCTCCTCAAGACCTTGCCTCTTCTCCAATGGAAGAAGATGAGCAG CATTCTGAAGCAGATGAGCCTCCATCAGACGAACCCCTATCTGATGACCCCCTGTCACCTGCTGAGGA GAAATTGCCCCACATTGATGAGTATTGGTCAGACAGTGAGCACATCITTTTGGATGCAAATATTGGTG GGGTGGCCATCGCACCTGCTCACGGCTCGGTTTTGATTGAGTGTGCCCGGCGAGAGCTGCACGCTACC ACTCCTGTTGAGCACCCCAACCGTAATCATCCAACCCGCCTCTCCCTTGTCTTTTACCAGCACAAAAA CCTAAATAAGCCCCAACATGGTTTTGAACTAAACAAGATTAAGTTTGAGGCTAAAGAAGCTAAGAATA AGAAAATGAAGGCCTCAGAGCAAAAAGACCAGGCAGCTAATGAAGGTCCAGAACAGTCCTCTGAAGTA AATGAATTGAACCAAATTCCTTCTCATAAAGCATTAACATTAACCCATGACAATGTTGTCACCGTGTC CCCTTATGCTCTCACACACGTTGCGGGGCCCTATAACCATTGGGTC SEQ ID NO: 153 Polypeptide sequence of Tet1CD LPTCSCLDRVIQKDKGPYYTHLGAGPSVAAVREIMENRYGQKGNAIRIEIVVYTGKEGKSSHGCPIAK WVLRRSSDEEKVLCLVRQRTGHHCPTAVMVVLIMVWDGIPLPMADRLYTELTENLKSYNGHPTDRRCT LNENRTCTCQGIDPETCGASFSFGCSWSMYFNGCKFGRSPSPRRFRIDPSSPLHEKNLEDNLQSLATR LAPIYKQYAPVAYQNQVEYENVARECRLGSKEGRPFSGVTACLDFCAHPHRDIHNMNNGSTVVCTLTR EDNRSLGVIPQDEQLHVLPLYKLSDTDEFGSKEGMEAKIKSGAIEVLAPREKKRTCFTQPVPRSGKKR AAMMTEVLAHKIRAVEKKPIPRIKRKNNSTTTNNSKPSSLPTLGSNTETVQPEVKSETEPHFILKSSD NTKTYSLMPSAPHPVKEASPGFSWSPKTASATPAPLKNDATASCGFSERSSTPHCTMPSGRLSGANAA AADGPGISQLGEVAPLPTLSAPVMEPLINSEPSTGVTEPLTPHQPNHQPSFLTSPQDLASSPMEEDEQ HSEADEPPSDEPLSDDPLSPAEEKLPHIDEYWSDSEHIFLDANIGGVAIAPAHGSVLIECARRELHAT TPVEHPNRNHPTRLSLVFYQHKNLNKPQHGFELNKIKFEAKEAKNKKMKASEQKDQAANEGPEQSSEV NELNQIPSHKALTLTHDNVVTVSPYALTHVAGPYNHWV SEQ ID NO: 154 DNA encoding Super exon (exons 45-79) of human DMD gaactccaggatggcattgggcagcggcaaactgttgtcagaacattgaatgcaactggggaagaaat aattcagcaatcctcaaaaacagatgccagtattctacaggaaaaattgggaagcctgaatctgcggt ggcaggaggtctgcaaacagctgtcagacagaaaaaagaggctagaagaacaaaagaatatcttgtca gaatttcaaagagatttaaatgaatttgttttatggttggaggaagcagataacattgctagtatccc acttgaacctggaaaagagcagcaactaaaagaaaagcttgagcaagtcaagttactggtggaagagt tgcccctgcgccagggaattctcaaacaattaaatgaaactggaggacccgtgcttgtaagtgctccc ataagcccagaagagcaagataaacttgaaaataagctcaagcagacaaatctccagtggataaaggt ttccagagctttacctgagaaacaaggagaaattgaagctcaaataaaagaccttgggcagcttgaaa aaaagcttgaagaccttgaagagcagttaaatcatctgctgctgtggttatctcctattaggaatcag ttggaaatttataaccaaccaaaccaagaaggaccatttgacgttcaggaaactgaaatagcagttca agctaaacaaccggatgtggaagagattttgtctaaagggcagcatttgtacaaggaaaaaccagcca ctcagccagtgaagaggaagttagaagatctgagctctgagtggaaggcggtaaaccgtttacttcaa gagctgagggcaaagcagcctgacctagctcctggactgaccactattggagcctctcctactcagac tgttactctggtgacacaacctgtggttactaaggaaactgccatctccaaactagaaatgccatctt ccttgatgttggaggtacctgctctggcagatttcaaccgggcttggacagaacttaccgactggctt tctctgcttgatcaagttataaaatcacagagggtgatggtgggtgaccttgaggatatcaacgagat gatcatcaagcagaaggcaacaatgcaggatttggaacagaggcgtccccagttggaagaactcatta ccgctgcccaaaatttgaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaatt gaaagaattcagaatcagtgggatgaagtacaagaacaccttcagaaccggaggcaacagttgaatga aatgttaaaggattcaacacaatggctggaagctaaggaagaagctgagcaggtcttaggacaggcca gagccaagcttgagtcatggaaggagggtccctatacagtagatgcaatccaaaagaaaatcacagaa accaagcagttggccaaagacctccgccagtggcagacaaatgtagatgtggcaaatgacttggccct gaaacttctccgggattattctgcagatgataccagaaaagtccacatgataacagagaatatcaatg cctcttggagaagcattcataaaagggtgagtgagcgagaggctgctttggaagaaactcatagatta ctgcaacagttccccctggacctggaaaagtttcttgcctggcttacagaagctgaaacaactgccaa tgtcctacaggatgctacccgtaaggaaaggctcctagaagactccaagggagtaaaagagctgatga aacaatggcaagacctccaaggtgaaattgaagctcacacagatgtttatcacaacctggatgaaaac agccaaaaaatcctgagatccctggaaggttccgatgatgcagtcctgttacaaagacgtttggataa catgaacttcaagtggagtgaacttcggaaaaagtctctcaacattaggtcccatttggaagccagtt ctgaccagtggaagcgtctgcacctttctctgcaggaacttctggtgtggctacagctgaaagatgat gaattaagccggcaggcacctattggaggcgactttccagcagttcagaagcagaacgatgtacatag ggccttcaagagggaattgaaaactaaagaacctgtaatcatgagtactcttgagactgtacgaatat ttctgacagagcagcctttggaaggactagagaaactctaccaggagcccagagagctgcctcctgag gagagagcccagaatgtcactcggcttctacgaaagcaggctgaggaggtcaatactgagtgggaaaa attgaacctgcactccgctgactggcagagaaaaatagatgagacccttgaaagactccaggaacttc aagaggccacggatgagctggacctcaagctgcgccaagctgaggtgatcaagggatcctggcagccc gtgggcgatctcctcattgactctctccaagatcacctcgagaaagtcaaggcacttcgaggagaaat tgcgcctctgaaagagaacgtgagccacgtcaatgaccttgctcgccagcttaccactttgggcattc agctctcaccgtataacctcagcactctggaagacctgaacaccagatggaagcttctgcaggtggcc gtcgaggaccgagtcaggcagctgcatgaagcccacagggactttggtccagcatctcagcactttct ttccacgtctgtccagggtccctgggagagagccatctcgccaaacaaagtgccctactatatcaacc acgagactcaaacaacttgctgggaccatcccaaaatgacagagctctaccagtctttagctgacctg aataatgtcagattctcagcttataggactgccatgaaactccgaagactgcagaaggccctttgctt ggatctcttgagcctgtcagctgcatgtgatgccttggaccagcacaacctcaagcaaaatgaccagc ccatggatatcctgcagattattaattgtttgaccactatttatgaccgcctggagcaagagcacaac aatttggtcaacgtccctctctgcgtggatatgtgtctgaactggctgctgaatgtttatgatacggg acgaacagggaggatccgtgtcctgtcttttaaaactggcatcatttccctgtgtaaagcacatttgg aagacaagtacagataccttttcaagcaagtggcaagttcaacaggattttgtgaccagcgcaggctg ggcctccttctgcatgattctatccaaattccaagacagttgggtgaagttgcatcctttgggggcag taacattgagccaagtgtccggagctgcttccaatttgctaataataagccagagatcgaagcggccc tcttcctagactggatgagactggaaccccagtccatggtgtggctgcccgtcctgcacagagtggct gctgcagaaactgccaagcatcaggccaaatgtaacatctgcaaagagtgtccaatcattggattcag gtacaggagtctaaagcactttaattatgacatctgccaaagctgctttttttctggtcgagttgcaa aaggccataaaatgcactatcccatggtggaatattgcactccgactacatcaggagaagatgttcga gactttgccaaggtactaaaaaacaaatttcgaaccaaaaggtattttgcgaagcatccccgaatggg ctacctgccagtgcagactgtcttagagggggacaacatggaaactcccgttactctgatcaacttct ggccagtagattctgcgcctgcctcgtcccctcagctttcacacgatgatactcattcacgcattgaa cattatgctagcaggctagcagaaatggaaaacagcaatggatcttatctaaatgatagcatctctcc taatgagagcatagatgatgaacatttgttaatccagcattactgccaaagtttgaaccaggactccc ccctgagccagcctcgtagtcctgcccagatcttgatttccttagagagtgaggaaagaggggagcta gagagaatcctagcagatcttgaggaagaaaacaggaatctgcaagcagaatatgaccgtctaaagca gcagcacgaacataaaggcctgtccccactgccgtcccctcctgaaatgatgcccacctctccccaga gtccccgggatgctgagctcattgctgaggccaagctactgcgtcaacacaaaggccgcctggaagcc aggatgcaaatcctggaagaccacaataaacagctggagtcacagttacacaggctaaggcagctgct ggagcaaccccaggcagaggccaaagtgaatggcacaacggtgtcctctccttctacctctctacaga ggtccgacagcagtcagcctatgctgctccgagtggttggcagtcaaacttcggactccatgggtgag gaagatcttctcagtcctccccaggacacaagcacagggttagaggaggtgatggagcaactcaacaa ctccttccctagttcaagaggaagaaatacccctggaaagccaatgagagaggacacaatgtag SEQ ID NO: 155 Donor sequence including super exon (exons 45-79) of human DMD tgggcatgtcagtttcatagggaaattttcacatggagcttttgtatttctttctttgccagtacaac tgcatgtggtagcacactgtttaatcttttctcaaataaaaagacatggggcttcatttttgttttgc ctttttggtatcttacaggaactccaggatggcattgggcagcggcaaactgttgtcagaacattgaa tgcaactggggaagaaataattcagcaatcctcaaaaacagatgccagtattctacaggaaaaattgg gaagcctgaatctgcggtggcaggaggtctgcaaacagctgtcagacagaaaaaagaggctagaagaa caaaagaatatcttgtcagaatttcaaagagatttaaatgaatttgttttatggttggaggaagcaga taacattgctagtatcccacttgaacctggaaaagagcagcaactaaaagaaaagcttgagcaagtca agttactggtggaagagttgcccctgcgccagggaattctcaaacaattaaatgaaactggaggaccc gtgcttgtaagtgctcccataagcccagaagagcaagataaacttgaaaataagctcaagcagacaaa tctccagtggataaaggtttccagagctttacctgagaaacaaggagaaattgaagctcaaataaaag accttcggcagcttgaaaaaaagcttgaagaccttgaagagcagttaaatcatctgctgctgtggtta tctcctattaggaatcagttcgaaatttataaccaaccaaaccaagaaggaccatttgacgttcagga aactgaaatagcagttcaagctaaacaacccgatgtggaagagattttgtctaaagggcagcatttgt acaaggaaaaaccagccactcagccagtgaagaggaagttagaagatctgagctctgagtggaaggcg gtaaaccgtttacttcaagagctgagggcaaagcagcctgacctagctcctggactgaccactattgg agcctctcctactcagactgttactctggtgacacaacctgtggttactaaggaaactgccatctcca aactagaaatgccatcttccttgatgttggaggtacctgctctggcagatttcaaccgggcttggaca gaacttaccgactggctttctctgcttgatcaagttataaaatcacagagggtaatggtgggtgacct tgaggatatcaacgagatgatcatcaagcagaaggcaacaatgcaggatttggaacagaggcgtcccc agttggaagaactcattaccgctgcccaaaatttgaaaaacaagaccagcaatcaagaggctagaaca atcattacggatcgaattgaaagaattcagaatcagtgcgatgaagtacaagaacaccttcagaaccg gaggcaacagttgaatgaaatgttaaaggattcaacacaatggctggaagctaaggaagaagctgagc aggtcttaggacaggccagagccaagcttgagtcatggaaggagggtccctatacagtagatgcaatc caaaagaaaatcacagaaaccaagcagttcgccaaagacctccgccagtggcagacaaatgtagatgt ggcaaatgacttggccctgaaacttctccgggattattctgcagatgataccagaaaagtccacatga taacagagaatatcaatgcctcttggagaagcattcataaaaggctgagtgagcgagaggctgctttg gaagaaactcatagattactgcaacagttccccctggacctggaaaagtttcttgcctggcttacaga agctgaaacaactgccaatgtcctacaggatgctacccgtaaggaaaggctcctagaagactccaagg gagtaaaagagctgatgaaacaatggcaagacctccaaggtgaaattgaaqctcacacaqatgtttat cacaacctggatgaaaacagccaaaaaatcctgagatccctggaaggttccgatgatgcagtcctgtt acaaagacgtttggataacatgaacttcaagtggagtgaacttcggaaaaagtctctcaacattaggt cccatttggaagccagttctgaccagtggaagcgtctgcacctttctctgcaggaacttctggtgtgg ctacagctgaaagatgatgaattaagccggcaggcacctattggaggcgactttccagcagttcagaa gcagaacgatgtacatagggccttcaagagggaattgaaaactaaagaacctgtaatcatgagtactc ttgagactgtacgaatatttctgacagagcagcctttggaaggactagagaaactctaccaggagccc agagagctgcctcctgaggagagagcccagaatgtcactcggcttctacgaaagcaggctgaggaggt caatactgagtcggaaaaattgaacctgcactccgctgactggcagagaaaaatagatgagacccttg aaagactccaggaacttcaagaggccacggatgagctggacctcaagctgcgccaagctgaggtgatc aagggatcctggcagcccgtgggcgatctcctcattgactctctccaagatcacctcgagaaagtcaa ggcacttcgaggagaaattgcgcctctqaaagagaacqtgagccacgtcaatgaccttgctcgccagc ttaccactttgggcattcagctctcaccgtataacctcagcactctggaagacctgaacaccagatgg aagcttctgcaggtggccgtcgaggaccgagtcaggcagctgcatgaagcccacagggactttggtcc agcatctcagcactttctttccacgtctgtccagggtccctgggagagagccatctcgccaaacaaag tgccctactatatcaaccacgagactcaaacaacttgctgggaccatcccaaaatgacagagctctac cagtctttagctgacctgaataatgtcagattctcagcttataggactgccatgaaactccgaagact gcagaaggccctttgcttggatctcttgagcctgtcagctgcatgtgatgccttggaccagcacaacc tcaagcaaaatgaccagcccatggatatcctgcagattattaattgtttgaccactatttatgaccgc ctggagcaagagcacaacaatttggtcaacgtccctctctgcgtggatatgtgtctgaactggctgct gaatgtttatgatacgggacgaacagggaggatccgtgtcctgtcttttaaaactggcatcatttccc tgtgtaaagcacatttcgaagacaagtacagataccttttcaagcaagtggcaagttcaacaggattt tgtgaccagcgcaggctgggcctccttctgcatgattctatccaaattccaagacagttgggtgaagt tgcatcctttgggggcagtaacattgagccaagtgtccggagctgcttccaatttgctaataataagc cagagatcgaagcggccctcttcctagactggatgagactggaaccccagtccatggtgtggctgccc gtcctgcacagagtcgctgctgcagaaactgccaagcatcaggccaaatgtaacatctgcaaagagtg tccaatcattcgattcaggtacaggagtctaaagcactttaattatgacatctgccaaagctgctttt tttctggtcgagttgcaaaaggccataaaatgcactatcccatggtggaatattgcactccgactaca tcaggagaagatgttcgagactttcccaaggtactaaaaaacaaatttcgaaccaaaaggtattttgc gaagcatccccgaatgggctacctgccagtgcagactgtcttagagggggacaacatggaaactcccg ttactctgatcaacttctggccagtagattctgcgcctgcctcgtcccctcagctttcacacgatgat actcattcacgcattgaacattatgctagcaggctagcagaaatggaaaacagcaatggatcttatct aaatgatagcatctctcctaatgagagcatagatgatgaacatttcttaatccagcattactgccaaa gtttgaaccaggactcccccctgagccagcctcgtagtcctgcccagatcttgatttccttagagagt gaggaaagaggggagctagagagaatcctagcagatcttgaggaagaaaacaggaatctgcaagcaga atatgaccgtctaaagcagcagcacgaacataaaggcctgtccccactgccgtcccctcctgaaatga tgcccacctctccccagagtccccgggatgctgagctcattgctgaggccaagctactccgtcaacac aaaggccgcctggaagccaggatgcaaatcctggaagaccacaataaacagctcgagtcacagttaca caggctaaggcagctgctggagcaaccccaggcagaggccaaagtgaatcgcacaacggtgtcctctc cttctacctctctacagaggtccgacagcagtcagcctatgctgctccgagtggttggcagtcaaact tcggactccatgggtgaggaagatcttctcagtcctccccaggacacaagcacagggttagaggaggt gatggagcaactcaacaactccttccctagttcaagaggaagaaatacccctggaaagccaatgagag aggacacaatgtag tcgtttaaaccgctgatcagcctcgaaacttgtttattgcagcttataatggtt acaaataaagcaatagcatcacaaatttcacaaataaagcatttttttcactgcattctagttgtggt ttgtccaaactcatcaatgtatcttagtaagttttttaacaagcatgggacacacaaagcaagatgca tgacaagtttcaataaaaacttaagttcatatatccccctcacatttataaaaataatgtgaaataat tgtaaatgataacaattgtgctgagattttcagtccataatgttaccttttaataaatgaatgtaatt ccattgaatagaagaaatac SEQ ID NO: 156 Intron 44 sequence of human DMD gtaagtctttgatttgttttttcgaaattgtatttatcttcagcacatctggactctttaacttctta aagatcaggttctgaagggtgatggaaattacttttgactgttgttgtcatcattatattactagaaa gaaaattatcataatgataatattagagcacggtgctatggactttttgtgtcaggatgagagagttt gcctggacggagctggtttatctgataaactgcaaaatataattgaatctgtgacagagggaagcatc gtaacagcaaggtgttttgtggctttggggcagtgtgtatttcggctttatgttggaacctttccaga aggagaacttgtggcatacttagctaaaatgaagttgctagaaatatccatcatgataaaattacagt tctgttttcctaaagacaattttgtagtgctgtagcaatatttctatatattctattgacaaaatgcc ttctgaaatagtccagaggccaaaacaatgcagagttaattgttggtacttattgacattttatggtt tatgttaatagggaaacagcatatggatgataaccagtgtgtagtttaatttcaacttgtggtgtcct ttgaatatgcaggtaaagatagattagattgtccaggatataatttggttgctaaattacatagttta ggcataagaaacactgtgtttattacacgaagacttaattatttttgcatcttttttagctcaaattg ttcatgttgcaatagtcaatcaagtggatttgaattgtagccaatttttaatgccagaaaatactgat taagacagatgagggcaaaaaacacccagtagtttattaaatactttagatatttcaaaatgctggat tcacaaaagcagtatcacatttgactttacaagtcttcattctcaaatatgtttccatagtaaatatg ccctttaatattaaggagttaagcatttaaacacctatttatatgataagctatttaaacacagaaaa tatttttaaaaccttgtgtaattatatgtgtatcaatcaaacttgcatgcacaccagcgttggcattt gtatagagaggaaatgtatggattcccaatctgctttaatatagaagatacattttaaaaatagcact gaagtgaattttgggctaatgtagcataatggggtttctgcctgagaggcagaaacatattagagtta tataaaatgttttggggtagatatagaaaccacttgccattttcaatgatatccaacccaaggtagtt atatatttcaatttatattttattatcaaattagtacttattgtgaaaaaaatcaagtaacatagaaa tttgtaaaagtacctccattctactctttggaggatagttgttcagtatgaattttgctacatatttc aggctgggtttcttggaaagccattgtaaaatggagatttgtatgtagaaggttaactagggagtact tttacgatgaagcaatttgttttgatgtaacttggtgtagttttcttcatgtttcttgttcttgaagt cagttaagctcttgaatctgtgcatttaacatttcatcaaatttagaaacctttcaaccattttttta aaaaaaatggaactccaattgtacatttattaggctccttaaagtgccccactactcactgatgttat gttcattgtctgtttggtctctcttttctctgtaatttttttatataatctctattgtcaaattgac taatctttttcaaagtctaatctatggctaatcccatgtagtatatatttttaacatcagacattttc atctcttagaagtaaaagttgggtctttttatttcttccatgtgtctactcaacatgttcagtcttta ctttcttgactatatggaatacagatataataactgttagaatattcttctctactaattttatcatc tgtgtctattctgggttaatttaaattgatttatttttctcctcattaagtgtgttgtttaactgctt ctttggatgactggtaatttttgactatatgccagacattgtgaattttaacttagcgcgtgcttgat acttcaaataaattcaaatatattgaaataaatattctcaaacctcgttctggaacacagttaattca cttggaaacaatttgatcttttgagaatcttccttttatgctttgttatgaccagaacagtgtaagtt tagggctactttttccccactactgaggcaaaacccttctgagtactctctctgatgtcctgtgaatg ataaaatttttcactggggctcgtgggaacaggtggtattactagccacgtgtgagctctggtgattg tttcctttaattcttttgtgaagttctttccttagctttgagtggttttcttgcatacatgaactgat caagactcagatgaagaataaaataaagctttctacaaatctccaaaatttcctctgtgtatatatca cctctctggtattttgccctgtgatcactagtcagccttgggctgctgaaactctcagcttcatcttt taacaaaagcctcctggcaaggatcactgtccttcaatgtctgatgttcaatgtgttgaaaaccgttg tagcatatattttgtctttttttttttttttttttttttaagtgtttcaggtgtttcaggcaggagat taagttcagcctcctttactccaacttgaaaacaagtccaaaacaaactattttgatgtaatttgatc ttttaatacattaacattacacaattttgtgaatatatcataatttaaaattttcagagaatgtctaa tggtcctcatttcttgacagtgtggtttagttgaaactgatgaacattttatcaaaacttttcccctc aattggatacttttttttttttgagatggaattttgcttttgtcacccaggctggagtggcatgatct cagctcactgcaacctctgcctccaggcttcaagcaattctcctgccttagcctcccgagtagctggg attacaggtgcccacccccacacctggctaatttttgtatttttagtagagacgagatttcaccatgt tggtcaggctggtctagatctccgacctcaggtggtctgcctgtctcagcctcccaaagtgctgggat tgcagacgtgagccaccatgcctggccaactggataattttaaaaagaccattttatttagtctattt tttctcaatctatagatgagataagaaaaatcattctagatgtccaaggaaaaattctttcagaaaag agctgtgaatgatatcacaaaccccccaaacagttaaggtatttctttcctggttattttatgtccaa aatcatgcatatgaacatgtgcacacacatgagcgtgcacacacacatgaatacatatacacgcacat aatgtaccttaggttatctttccattctgagtaattatcgtaaaatgggtaaaatcaaccccgtaaga taccttcatcgataaggcaaatcaaagctttggtaatttctgctatcttggcctttgttgattgacta ataatgaataagagaatgagtttcaatatttactatgaaattattttagaagacaggatgtagacagt ggctgttagcaggcaattgtttggcatgagccagtaatggttactgtgaaaaaaatcaaccaagcagc ccatatattaaacaaacacacgcagaagcacgttggagtctgaagcctcatatgtacaattttcagta aagaaataacttttagatatgaaataaacaaatagatatatgttgtaaacttgtccctatgtattttg atcaaattgcatcatatttttttcactttaaagaagagaatttagtgctttaactgagacttagtgtt atcattcaaaatatactgactgccaatagcagtagaaagataatctggttccatgcaactctattttt tttcctctgtcgcaagtaaaagacaaaattaagtacatgaattagtgctttttgaagatattccagag caatataccatgccactatggagaacctctctaaaaatatcccatttttttacctgagaaaaatattg atcatgttatatgccactcaaattggtttattaaattcgttgaatgatatcagcatctcttaatgcat tcactaaacaagcagtaattgagtgcatatacaaagttttatcatccaccaaaacagtgacaatccac atgaggctctaatagaagtttagaaagggggttaagtggttaaatgctggactcagaaagattggatt caaatcccaggtcctttagcttaatagttgtagaatcttgtgaaaatatcttaattcttttcatgtct ctgatttctcttctctaaaatggaaatataaatgagatgtgtataaagccacttggaatagcattttg cacaaaataattactcattaaatgtaagcccctattataactaatcactctttataagtgattagttc atatcaatacaaactaagacttatttactgaattatcgtctctaaacatccacactgcagaaaaacca acctggaaatttcataaaaccttatttttatgtagtataatttcttctcaaagcataagggctcttgg attaggaattgaggaaaattccaattcagccaaacgcatctgtttcagatagctgacacttctgccta ctcatttcctagctaacaagaagaaatgttaatgggagttttcaaaggaaaagctgaacaccatgaag gaaagtgacacaaataatgttagctcatatattgacagggtgaatttgtgtgctttcaagtcccttca gtgaaaataggaaagtagaaattataaaatgccctaacatttaaagctagcatgttcttggagactag gaaaaaataagttttaaaacatgggctatgatagaatgagatggaaaatgtttgtagttgccagtaga aacaataacaattaccattagattaagtatttaaaccagctgaatatttttattaatggaaatggcat ctgttttatgaaataatgctgctgaatgaaccatattaaaaatgaccagtatttcctgcagaacgttg tcgcagacatacaagcctgagaccctaaaatcttaaggtattccatttgaaatcgaccttaagacatt aacagtagtggtattgtttagatgaaattttttaggctttaaatcaacaaatgttaagcagacatggg gagcgaaacaccagtgtgttattctgacatgaataaactgctgtttttagggaaaaaatatagtcttg ttaaggttaagctaattggttttctggtatcttttgcaatgttagtgtgttttactgctccataacct atgttatatggtaaatgtgcaatatatttatatatgttgctgtaaagaaatgtaataaaaaactgttt actttgtgatatgaaagtaaaaatttattcattgtcattgagcatacagaagtaaatatggattacat atgtcatattttaatgttcacatggtcccaccatcaaatgttgaaaaacttatagtttaacgtcatat tctattgaagaaaaatacactcccttttctcaaatgtgaaatgtccagagagaatggaaaattacata taaagcatgtagttatagcatggtgaccctgctgtgatctctcagatgaggaacaaaagggagaaaga aagagcacactggtgctttggagttgagagaaggcaaaaaaagagtacaaaaatgtcaaagccaagtt tagctgctcttcagctctccctttagctgctcttcagctttaccttaccatggttattagtgattgaa gaaaattctaaagcactttttaaaggacccaattctgaagagtttagattcagagagcacaatggagt tggagtgactcctgctcaaaagtttgagacaagcgagtccatgaaaagaccgtcctcctcttaatgga aatacccaggttttctcattcttctcgccttgctttcagcactcgcagcccagaaagcccttatctaa caggtactgccgttgaaaggtcattgacttgtacaaaaatgatgagtgctgaatagatgtgcataggt cactgacagtatctgctacagagaatgagttttcgtatttttattaggatacacctaacatggcaatc tactgcctcaaagaactctataggaggtaagtgaatttatattaatacagattgaattaaaggataat ctagaaaaaggcatatgatgtaaaaaaatcagacacaagtatattttctgtatagtcagtttttacat tgtgatttcaccagctggctgctgagtttgacggcttcttaacagccacactgctgagattcaaatgc tgatagaaactttgatggaaaaatcactggagtaaatatttctaccatctgttgcccttcactgggac cctaacgttaagaataattcataccattgcttgtcctttatatttccccagcagtaataaaatttcat aagattttgttttgtggtcacaaagctatcctggtttctgtaactagaagacatacactagcataagg gaatcagccggaaaatttactgctaagagaatttgtctctagtcacttactttaaggttacagcaatg tgtaagtgtgggaatacattttaaaatgagcttttcaaagttattagctggtagtggcatgagagtta agtctcttaatacagttaaacagttgggcacttcatccttgcgtaaatattgttacccttttattgct gcttggaaactcctctgcaactttttggcccctatccatcttttcagaagtagtaaataaccaattta ctgggagtgtggtaccaggcagaaattccgagaggggctttcaatccttgcccatcaagtgtatcttt cagaaataagtatattaaaataattggataatttcagtggcttgttattagacttccgttgtccagca tggcatgtttaagaagatgacagattttcatacattattggaaagaagcaagaacaaaaaaacataac ttactgtagtaaccacggtaaagaactgcttaaaatgcaggataaacatgtcatccctaagggattcc cattcttagagcatgaaattatcaagagagtaagagactacaaaaaatgagaagaatgctgattgcaa attccaaatagaaaaaatcaaaacaaaactgcgcaccatcattctggaagcaatgagaagcagaaatt gtcatttaatgaaatgtaagattaaagttaatagaagtaattttcatgaaataatattttgcaaggac gatgttccagccatattgatcttcgtgttttcttttcacatcccttcttactgttccctagaatgctt gtttctacctttaaatttgcttttctctctaccagagggctctaccctatctccagtttctcaccatg tcccaatctactccctctcagaatttttgtacacttccctttatatatatttgtgctctaattttata ttcacagatatgccttttgtaactcccccatcttaaagaaagcacacacgtacgcacacatgcacaca cacaaaattgaactctttctgggagatctgcttaactttcttcataactctgtcacttgctgaaactg tagtatgtgttttcatgtttattatcttttccattagaatgaacatattttgggtacttggtctttct cgatcaccaatatacctcggtacgtagaaaaattgattcatatattgaaaatgtaatattcagtagaa cgaataaatacataaataaatttaaaaatgatacttttattgtattacctgagacaaatgatccccaa gtttgtccttgcttttcatagccaaaacattctctcttacattgagcttccttcacctcttctgtgta cagagcacttaaaattttcacattgcctgatactttaacaatatgatggccctgttctcttacccatt ggagcatatgttaaataccagaacccatgtaacaaacatatattgtgatcctactgtgtgcaaagcag atactgcttgctgctaggaatacagagctgactaagagctccttttctctttatgagctcacagtctc atgagttcaacgtcttaaggcacaacgtctaaagcaaagggcagtaagtaaacactccagaaagtact ggatctggcctaggacaaatggtgggttgtttttccagctgttatttttcctgccccctaattgacag tcctccattacacctctgggatacctagtctgacttgggaaaacctgactttgggaatcagaggcagt ctctcttgcttatatatgaggaactctaatggatacttactgtcattagagaaactctgcttctagcc tggctccttttgtaaagaaggttgagtccccttggagagcctgcagaacataaccatttgcatgtaat gaacagtttgtaatactttgagattgatgtgcaatttctatttgacaagggaaaaacaattaggatta accgtggtcgtatatcccagaataccaacgttgtttccacactctaagtgttgttgggtcattatatg agattcataattttgtcctgttgtacccacgtttgcattaccattcagtcttaatttattatacccta ttaaaagtttttttggtaatttgttcttattgctactcaggcattaaaatgtctgcaggctgtgaaaa tgaataaatttaatgtggcagcatagttctcaaaatcctggctttacaactcatagtacaggcttgta ttgtaaatcctagttaacatggatttatttgaaaatccaattttactgctaatcttaaataacacatt tttcaaacattttatccttgaatttctatttttttataatttatggctgttgtatgtatttacaaaag gacaatgtgtgtacttttaaatactagtaatggattgctgaaacaactgtaactttaaaacaatgcaa ttgttaaaaaaataaactgtgcagcctggcttaatggaggcttatgaacatatgattaagatatatgc tataataagcaaattcactcaactgatagttcataggaactttcaaatttaatctcataaccagtgct atccttcaaagaatggtcagggcaatttaacgagtacatgaccacgcaagataatttcattgaagagt ggctgaactgttgaaatattttctagtctccttgggatatcattaagagcagaaattttgaaatggaa ttgtaatgatgttcagaaaagataagtaggtaactctcttaatacgttttgtgctgctgtaacaaagt acctaagactaggtaataatttgtaatgaacaaaaatgtattggctcacagttctggagactaggaag tctaacattaaggtgtcagcctctggcgagggcctacttgatatgtcatcacatgatggacgattaga gggcaagaaagatcaaaagggggctgaactcccacttttataagggaaccaaacccactcgtgagggt ggagccctcaatccttaatcacctcctaaagctcccaccccttaatactgtcacaatggcaattaaat ttcaacatcagttttggagggaaaaacattgaaaccatagtagtgatactgactactaccacacaggg cttgggaggctaccctagctgttgcacccaagagatgaatcttctaatgtgattacctttatcatttt ttttactttattaaaatacttttattttacatgtatacttttgtctacccaccatttccatgtctgac cactgctactactatgtcctagcataacattccatacatccttaaaaccaagcaaagggtggagttcc atctttaaaaactaaacaggcattttggacaacacattcttggcaatggaatctggacaacatttatc aaacatggtagggaaggttctcactctgcattatcaaaacgacagccagatatcaactgttacagaaa cgaaatcagatggaaaatttttaacaaattgtttaaactattttcttagagagacttcctccactgcc agagatcttgaatagcctctggtcagtcatctggaagcaattcttcacataattcatgaacttggctt ccactttaggaagagaaccacctttttctatacttgcttgcatttttgctttaatgtcttctacagaa ctaggtcctttgggtgttttaggagtttttccttgttttgaaggattcttgtccttttgatcttggtg ttgacggttttgagtcttttccattccgatttgacttttgtgcatttttggctggagtatctcatata gatttcttcactggcgctttttcttcagtttcctcatcatcaaaatcatcatcatcatcaaaatcatc atcttcatcagcagcaagttttacttttttctgtggaaccttgctaccacctccaggagcagatcgct ttccagatatacttatgagtttcacatcctcctcctgttcgtcttctgactctgtatcttcctcccca gctactaaatgctgtccactcacatgcactggccctgaaccacacttcaaccgtaagaccactgatgg tgttatttcaaagccctcaagggaaaccatgggctgtacagacattttcaaagctgccagtgttactt taattggactgcctttgtaactcattgcctctgcttcaacaatgtgcaatttatcctttgccccagcc cctaaactgaccgttcttaaagataactgttgctcaatttcattattatccaccttaaagtgatcatc tttgtcggcctttagttcacaaccaaaaagatagttttggggcctcagaggactcatgtccatcatcg tccatcaggtggcaggacgcacttaggtgggagagaaggcagatgatgataaaggaccactgctcaag agaacagctgtgcaggacagaatcacaccagggagattacctttatcttagaaaacctgaacatcttg tgtactttgacacttctctacatttcacctaacctttaacatcaacacatttattcagaaaactttta cttttggagctgctctgtgtcaggctctatgctaggtgctcaggatattgaaattgatacaatcctaa cctattcacatataatccaaggtttgctgaaattgatggacatttaaacaattgaaacatttaagtgg tataattagcaaatggacatttaagccataaaaatagcatctaatagatataatagaggtcggtacac cattgatgagtcagagcagaggcaacccaaagagtaactagccagaagaattgggaaagcttcataga gagagcgatatgaaaataagggagagaattgtaaatccatgaaaatgagaaaaagttgaaaagtgatg gtgtcagaaaaacttgtggtatgataatgacaagatgagaggaactcttggtaagcgtgttggatgca tggaaagaaatggcacaaaataatgctgaggacattttttattttattgttggttttgttttggttaa tttcattttttaaatctagtatgctagtgttcattgtccaaactgtgaatcataaactcagtttgtgg atcaacaccggcctttgatttttagtgaaacaaaatagaaaatatcagcattcatcacaaatagatgt ttcacagattttttgttttaattgcgactgtgtgtgtgtgggtgtgtgtgtgtgtgtgtgtgtgtgtg tgtgtatgtgagagagagagagagagagagagagagagatggcttggatgtttatcacctccgaatct tatattgaaatgtgatttccaatgttggaggcagggcctggtaggtgtgattggatcatgtgggtgga tccttcatgaatgatccctttggtgacaagttagttcatgctatatgtggttgtttaaaagagtatga gacctcaacccccacctgtttcctgctctcccctttgccttccaccatggttggttgtaaacttcctg aggctctcaccagaagtagatgccagtgacatgcttcctgtacagcctgcagaaccgtaagtcaaaag aaaaccccttttctttttaaagcacccagtttcaggtatttctttatagcaatgcaagaagggactaa cacagttgtatgtgtatgtgtgtgttgggtgatttctggttgagtgtcacaaggttgtaatatggtga gtgtaaggaagtataagttttagaaaattaagaagccagttcagaaaactaatacttttggaaaatag tacaaaatcaactttacaagaatatacacagaaagatgtaatacaagatttatttcattgcagtaatt tataaagttggtttagtgccttgcttttgcatgctgttttaaaaattaccaagaatatgacttcatgt gattttgaaatactcccagcaagataggtagaaaaggtattcttataactcttagacaaaaatttcgg aaagtttaaacgctttatcccaaatcataaagctaataaatgaagaatctgggattcaaacaccatat tttttttactgttcatcagctagaagttagaaatgttaagccaaaaacattaagtcactgctctgcct aataaatcttgaggaaactaataaaaagaataataccactgactacaggacaaggtcttcctaagaga ccttaaatatattaagtgatgaagatgaaacttcttttattcataaaaatgttatttagttatgagta gagctctaattaaacttattttatattgtcatcagtaaagttgagacataacatatttattaatataa ttataatttgacccatagtgtattaaaagaaggatgttaaaaggagttgttattagagatgatgttag ggttgttgatgataataacagtagtcataacataacaaagcacttcataatttaagaagtgccttcaa ttacattgttactctcatggtaatctctgtttgatatatagatttggcggattctatatcactctaag acataggttactgaggtgacggaggaatttagcaagcggctgtcaaatggaggacatgagcattggat tgtgtatggcaagggctgatggtctctaagaaagcctcttggtttccacagggcagaagccctttgaa gatcatagccaaggatttagtaattgcctccctttcagaataccctcaagagaaaagcccaccataag acatggttccctacaggcaaaactgcttttccttaaaatttactgttccctgaatatcagccttcttt ggctcattcaacatagttttcttaagtttcaggacagtgctgcagaccaaaagtttcaacattgagga aaacaatactacttgtgcagtgaccctacctcagtcagggaggcagatgcctgcctttatgtgaggga ataaggaatcaatcatatttccagcactcaagaaagccagtctagtgcagggagagatagatacataa acctcaaagttatgatatagcataatagttttaaatttccataataactgtattttaaaagttttata gaaacagaagagatgacctcagtctggaaaagccagcttggagaatggcaaccaatattaagtggcaa aagctttgggatcccaggcctccagatggagggtgatagcatgggccagacaggtaggttaggaaaac tttgcaaaggacattacacggtacacagacaagtctgtgttttagcctataaaccacagttgcagaat gtgtttgagcaaaggcttttggggatgagatttgcacttttcaagatttaagtttgtttaggatactt acggtttgctgtatacttcctgggtttttacattataattacggtttgaactttaaaggaaaactgca gtttagcatacttgaaagagtgcaacttcaagtcatgattggagacagatatttaacagattttgtga tcctgtgatgcttattttcttctcagacataccacatgacaatcatttttaaacagtttatttctact ttagcatccatctgaaggtgttgtgtatgttttctgcttgaaaataaagcagtgggctgggtgcggtg gctcacgcctgtaatcccagcactttgggaggccgaggcaggcagatcactaggtcaagaaatcgaga ccatcctggccaacatggcgaaaccccatctctactaaaaatatgaaaattagccaggcgtggtggtg catgcctagagtcccagctacttgggaggctgaggcaggagtatcgcttgaacccgagaggcggaggt cgcagtgagccaagatcgtgccactgcactccagcctggcgacagagtgagactctgtctcaaaagaa ataaaaaagaaaataaagcagtgaatgcgattaagatggatttattatgatcataaagtactcaggag tcttattttaaaagacagcattactgtaattaaaaatatagggaagaaactaatgctgttttgcgtat cattctcagctctctcaaaatcagatattaagctcttgctgccaaaggagactatactgcacggtgct cacctgcataaactttgagagggttgaattgtgccaagcaattctctcaatacataaattaaccaaat atttgttgacctactgtgtgacaagtattattccaggaaataagagatccagcaatgaaacaagtatg gcttcttatagagttcccaaaaaggaaataaaaggatatacgtatagtgatatccctgaattaaattt ctcttttgaaaataaaaattctatcataagctgtaactgccaacacttcaatactcattcagcagttt tcagggatttgtaccttttgacttatgagaatttggaagtctaattgtatcattgcactggagtctta aagaaacagataagcgaatgactttgcctgtatcattgttgactgtacttacaatcagaaaggggcac aggacagatgccagggagtaagtggacagcccataaatggaatggtaagaaagaagaactatagtgga tttggaaagttcccttcagcattttccctagacaatctttggctgtgtttgcatgatcagtatttcat tcacaggatattgagctcttgatatagttctcaaaacccaaaatgaaataagaagtctactctttatt taaattcaaattccagagagttaagtaactttccaggaggtaatctaaatatggcctccttgttgggg ggggggggggtgtttgaatttgcatataaatagtctcacccttaaaggaaaaccacagatggtggtaa tgatgtagtcataatgtacatctccacagtggtggaacaaaatatccacagttttgctttccccagtt tcagtgacccatggtcaactgctgtctgaaaataggtgactacaatacaataagatattttaagagag agaaagaaagatcacattcacatgattttcattacaatgtattgttataattgttctatttttattca tgatttttaatctcttaactgcgccaaatttataaattaaaatttatcacaagtacatatagtttata tagggctcagtactatctgcagtttcagacatccactgggagtcttggaatgtatcccctacagataa ggggtaaaccactgtatcctatttgtgtgaatgctacaggtgttgtgagctcataacaatatgacatc aacactgaactaatccaggatttggtagtgagagtgatgtatttgcaaggagtgagacgtggtgcctc atccaagcagagaaataattttgaaatttgcctgacaataaaaatcacaatgtgaggtctctctttag agctgcaaagtccaattcagtgccccctagccacataagatactgagctcttaaaatgcggctagtac taattgagatgggcactgagtataacacacatgccagggtttgaatacttagaaccaaaaaggaagta aatgctcatttattgcatgttaaaattatggttttattatagttgattaaataaaatatataattaaa ttgacttcattttgcttttaaaaatgtggctatgaaaaatttcaaattatatatgtgtgtgattacat atgtgtgttttcacatatgtaactgatgttacatgtgaaattgattgttacatgtgacatgtaaaaca cgttacctaacacgtgcatatgtatgcaacacatatgtaacgtgttacatatataacacgttacatat gtattgttacatgtgtgcttgcattacacacatgcataatatgaaattacatgtaatttcaaattaca tgtgtatattttgaaaattacaaattacgtattttgttatttttgctttacaaagtcaaatttaccct atttaataaagcatcatgagttttttataactagtaaactttgagacttttgtaggagaataaataat gcttattataaaaactgattggaaaagtgagctggagcagggagcggaggaaaaaggactagagatca cctttcttcccagctccgctcctctcccaaccttttttctttccattctctcatcccaattcaaaagt gcagagttcacagttggtgtgctgatttagaaaacagatatataaacagccttaaattttctccaggc ttttacaatgaaaagaagttcaatatcaaaagtaacaatataatctgtggaaaggtatagggggctat gtttttgaggtagaaactataggtgctcctggccaagcatggtggttcaagcctgtaatcccagcact ttgggaagctggggcgagagtattgcttgagcccagaagtttgagtctagcctggcctacagggtgaa actccacctctactaaaaatacacacacacacacacacacacacacacacacacacacacacacacaa aagccttgcgtggtggcgcttgctgatagtcccagctactcaggaggctgaggcgggaagattgcttg aacctgggagacagaggttgcagtgagctgagatagcaccactgcactccgacctgggtgacagagta agactgtctcaaaaaaaaaagaaaagaaagaaagtataggcactccttatatgcagctgctcacaccc ctcctccttcacacccctcccccttcacacccctcccccttccccaaaatttgcaaggggaaaaatgt gtgtaattggcagtatttagtggcgtgcaaccgtgagtcatcagactgcacatcctcacttctgctag tggctcagtacccaacagcactcagtgaaaactaactcatttcaaaggtgaaaacaagtgagtttggc caccagggagtgttcaaaactgtcagtgctgaagcaaatgtggagggtgttctgtagtttgttcaggt tgatatttgtggtccaacccctagctgaactactaattattaatatctgtcttgatggtgcctcagga gaaagcttctcaaagggaatcaatgttcaaattatagtaggtatcttggccatggaagttattgaatt ttagccaatacttgctactctttcatttatagtgtgagaatgcagtgtaatgaacctgactctcactg tcctgacttgcctttctcatcgcattcacaataagcacgtcaatacgtatacacatttcatatttcta aagtttactttatttccttattgtacatcgctgtgctgctgatggaagagaaaaggaaaaacactatt gattgcaaaactgttttatctttggtggcttagattttttttgtatgatatgtaacgtcttgcatacc taaggcaacacgaagctaaatagatttgcatatagcatgtattttttccaattaaatgtttaattttg ttcagagtatactggggacattttgaataatggagaaaagtacaaagaaaattcataattctaccacc tatcagcacagtgaaattttatgaagaaacataattttcatgtaaatcatagtgaactcacggtaggt tttatttaatacagtaattggagagctggtaggaagacaaaactggttcaaaagagaatacaagaaac aaatgcttctataatgagtgaatttttaaaaaagtattctggaataagattagtgaataagatactaa actcgttgataccctacagcctttggggttatatcctctactgggtaaaaagtcatttacatcatatc agttttctaaaatttgcattgaacttcatagcgttgtaacatgtgtgggcccaaattaatagtaaaca gtaagagttgctttactctgaaaatattgaagctcttgtgagggtgtgaggagtttgttagaaaacaa cgctaccattattttgaaacacacacgatcatcttttgttttacttctaagttttggataatttttct taaattatcttattatcttatccattttcttaatttccttaaccttttaaatgtttctcctaggcact tttattgatttttggaatatagttgatatgtgctgaatttttatcatccagttttaattctactgaaa aatctaaaagatgttcatcaactactatatttcaaatgcatacatcccctttcatgctaaagaaactg tatgggaaacacagtctgacattttcaggacctggtatcattaaaagtcttgacactgttaaaattaa acaacgccttttttaaaatcaaaggatacaaaagggctgtgttggtcagaggatacaaaatttcagtt agataggagacataagttcatgagatcttttgtacgacatagtgactataattaataataatatgttt tcgaaaattactaagagagtcgattttaagtgttctcaccgcaaaaaaatagtatgtgaggtaatgca tatgttaattagctcattttagctagtccacatttttcaatacaatgtgttgtataatacgtgatata tacaacttatattttccaattccaataagtaaaaataaatgtaaattatttgaaataaataaaatgtg aagaacatccacttttcatatgaaaccatgagatattttctgttaaaagattaaatgtccaataaatt tttgatgttaacagaaacaaaaatgtttaatatttaaatacatatttgcatgctattgaccccctgaa gttcactgctgggctaagtgaaccaactatatcttaagtcaaaaatgctgaaattcttccccaaatcc caaagctcatgaaaacataaacagaaaatttccaaataattctacagggaaaataagacacactattt gatctgatcaaacaacgggatgattatggttaataatgagttacttgtacatttaaaaataactaaag gagtgtgattggattgtttgtaacacaaaggagaaatgcttgaagggatggataccccgttctccatg atgtgattattacccattgcctgcctgtgtcaaaacatctcatgtaccctacaaatatatactcctac gatgtacccacaaaaattaaaataaaaaagagagggacccgaagataagctaatatttaagctcatca tacttattaagataagcaatacataccgaaagtaatagcatttaaaaccagatgttgggggagggttc taacttcttcattaaaattcaaagtcacctgtcttgttttttcttttgtttttgtttttttttttttt tttttgagatggagtctcgctctgtcaccccaggctggagtacagtggcgcgatcttggctcactgca agctctgcctcccgggtttacgccattctcctgcctcagcctcccgagtagctggtactacaggcgct ggctaccacgccccgctaatttttttgtatttttagtagagacggggtttcaccgtgttagccaggat ggtctcgatctcctgacctcgtgatctgcccaccttggcctcccaaagtgctgggattacaggcgtga gccaccgtgccaggccacctgtcttgttttatcatgatcccgagagtatatatgtatgtgtacagctc atctaaaccctttttctttcaacatgatcaatagattgaacattggagatattttataagaaataatg aagacaactcaatcagcacatatatatattaaatgtggaatctataatgattgcgaagcctgaagcaa actaaatattcagtaataggttctttttttccatggtatatccatttgaatatataacataaatgcct tacatttgttttaactatttaaggtttatgttgttagtgtgatgaaatggctggcaaaagtcagaaac tcaggaaagtttcaggcttatatctggagcctggttttctttcttcaaggtagaacctctgtgaagtg aaaaattttttttatatctggagcaataatgtagaagcttaaatgtattatccaagttgtcataagcc tattatttctttacattactgaagtgaaagacagcattaatggctaaatgccatacttggctataatt tatattgtttaggactggaaatgagcctgaaatgtacatttttttccaaaatagttcatgtaatattt gaaacctgacaagtaacctgatgatttcatggaataccatcaaatataaatgtgaagttttaaagaca cagggaaatactcagaataaaccccctaaccacaggccagcagaagaactagacttgagaaaatgaat gggaagatagatagtaacaaatgacttctttggcagccttatatatgcttagtcttatagactgtttt atggatgctctgcactctatttccagcaagtatggcatttggaacaggaccacacgagacaaactatg agttcacatttcccacaactgcacagatagaaagagggaacaacagaatactccctttcttcttgaaa caataacttctgttgaagctcactggcttcttttcagctgtttctgctagctcctcctccgcctcttg acctctaaggcaatgctcttcaaaatttcaagactgctttctaattgaaacaaaacttataagcacat ttcttcccacaaaatgtacatttatttgtaaatcatatatgaatatgactaagcatgtaaacgtatgt gaaaatagaaatcaataaatataaatgcaaacacaaatagaagcattcacagttttcttttgtgtccc agtgagttgttccaaattcctcggaggtaggtatgtcacagtttgagactataccttcaatcctaggg tttctggtttcgctctcctcctaggtgatagcatccatttctacggacttaactgccatctttagttg aataactcctctatctttccatcccatatttctcttgattccaaacctgcttgttcacctgagcatat gacacaattcattggctgccgcacatgcagctttgacattttatttaaaatctttccccttccccagc cctcatctatttcacagtagtatcttcttcttatctacttgattggtaagcagagtccacatgattcc atcatttatctcccattttatatctaatctataagcaagtaatgcaatgcaacttctgtctccaaaaa tttattttgaatttgccttctcttcctctgcatctcccccatcttaggccaggtcacctctgccctct tgccagattaggtcacattctcttactactgttgttattctcttcctattcaatcctacaccgcagca aaatggatcttctcaaaatgtcagctagataaaggcatttctgtgcttaaggccctcatggatttatc ttattaggatgaacacccaactctttattatggcttagaatacaatgaattacaacacataatgaata tattatatttctatctttaccattttcttcttaagtcaacctttctcaatccatataggataatcata ttagtgcttcctcactttctaaaacatctcagggcctttgcacgtgtttctctgttcttagacccaga atgctcttccttttctctttgtgtagctaggtgcttctttccatttacgtatcacatgaaatgcagtc attccctcctccttccctcactacctcacaaaaagttgatgcctctgttaaaccatgaatggaatttt actcggcagtgaatagaggaaaaaccaatggtaaaagcaaccatatgaatgaatgaatgtcaaaaata ttatgctgagccaaaagtcatagacacaaatatgggtatttacatgaagttaaagcacagcaaaactc aattacggtaatagaattaagaaagtggttacctctgggtgagggttggaattgagtggacagaggca ttagtgactttttcggggtaatggaaatgttgtctattttgttcaggtggtgaatacatagatacatt caattgtcaaaacacatccatccaaacacttagacttttgcactttattatatgcaaattatgcctca actgaaaaaagtttgttttcaaaattatatcaacagttgaaattcttttaaagatttgattcaaatga gattaattctgtatccatcattgatgtatgatagttttgtatgtagttaaggttattggagataattg aaagttatactcacaagaaggctgcataatatgaagtttatctgccttgatctttaatagctttcgcg atttcaacttcttcacagctctgtaagaaggcagtgtggcatgttgaagcaagcatgtgttttagagt aacacagagctggtatacaaccccatgtctaccaattatcaatgatgtgggtatgttgctggatctca ataatcttccactgtgaaatggaatgtaacacctgactcacaacgcaaaggtatttaccttatgtaat ataattcctgcgatcctgggacctcccttaatcccatccacagatgccaggttaaagaccccatcaca gactagaacaagttgggatgtcaaaatgaataaatattaatcgaagggcctattgtgattgaacacca cgcagtaggcactctctaatacctaccgtctccctcctttttgggggaaacattctaaatgtgcaaaa aataaagggttatttgctttctggcacttgggatcgatttattgaggatatgttagcagaacagcaaa ggtgaaacactaaaagcaccatcaatacacaggcagaggtgaagccataaagcctttattttttaaat taatgcacaatatataagaggtatgttagaatgaacgtccaatccctgaaaggatatacgaaagacat tcataaaattacatgggcatgttttcttaatgttcaaaatattgttttaattagtgtattatgagttt attcatgtgtctgtgtgttgtgttatattaatcttttcttgcattgctataaagaaatacctgagact gggtaatggatgagaaaagacacttacttggctcacagttctgcaggctgtaccggaagcatagcagc atctccttctgtggaggcttcgggaagcttccagtcgtggcagaaggcagaacgggagcaggcacttc acctggctagagcaggagcaagagagacagaatgaagtaccacacacgtgtaaacagccagatctcag agaactcactcatcatcatgaggatggcaccaagaggatggtgttaaaccattcatgagaaatccaca cacatgatccagtcacctcccaccaggccccacctccaacactgggaattacatttcaagatgagatt tgggcggggacacatatccaaatgatatccatgtttaatcagaaaaataaaagttaacagtaacagtg attttactttgtagacctttgctaatggctgaaatctagctccattccgagaacagcctgcggtacac attttgaaagatagttgattaatatgaaagaagccttatctgtagtccttaaggccattatggtttac atatatgagtaaatattccaaagtagccatgccagttaacatatatccagagtctaaaggccactggg cgacaaaagtaaaagatacatagcaattgttactttatatcacagtaattcttgtatattttaaatgg atatttgcatttgaggatatccacttaagagttaggtacatggctcttacatttaagtaacatttact taaatttctggctgcagcaattccacataggtagaaatgaagtctgaattgagttgggggtctttgca gtgctctctctgttcattggctattttgacaatgctgagagatgtggttagccattctttttcatttc atattggcaacctagagagcaattaagccttctccccttaactagatgtatgttttactcatttctgg atctttatggctgactttgaatcctagcctgtggtagaaagcatggtgtcagaaggaactatgagtta agactatgcatacttggctttgagtcttgggtatcatacctccctcatagagtgaaggaaccagggat tcttcttgaggcccagacccggcatccatgttaagaatacctgtgcaattttgcttcctgatatttaa ggtgaaaatgcatgtttgggtcattgtgaggattatgtgagatgttacttttaaatataggccccctt attatatgctctcatagtttcaggcaacacttgtcgtatttgtaacctcagttttaactgtaatgttt ccatcaatgtccctcttacctggtacaggggctcttcatattcttggattacaaatctgtgaatgcaa ccatgcatcaaaaatattcagaaaaacaatgaatgcctacctctgtactgatgatttataggtgtttt tcttgtcattattccctaaacagtacaatgtaataagtatttatatagcatttacattgtattaagta ttataagtaatctagagatgttttaaagtatataggaggatgtgtgtaggttgtatggaaatagtatg tcattttatatgtcacttgaacatttgtggatttgctatccgtggggatcctggaaccaatcccccat ggatactgagggacaattgtattataagcagcaagagggaaaggaatctgtctattttgcccaaaatc gtgttcccgggacctagcatagctcctggcaaagagtatacaacaaatatgcattgaggagagaacag agggaaccattatccccttattctcgctgttccttcatgtaatgaataaacagtcaaatcttacaaga gattttaaaccagtcagagaaaagttggaagttagttagttgttcatacattgagaagcctcgacgct gtgtcatctaggtaatgaaagatctagggaagtttagcagggagaagaagagagatgatagttgtctt caaatgtttgaaggactgttacggacacaaaaatttaaacttgtgctgaataattccaagaggtacac agtctctcgatagaagctaaagtggggggtgacatttgactcaacaaaaagccatctaaatatcagaa ctttcaaaagcaggaactggtgcctcaattaatagtgtgttttctagcacttatgatacctgatcata ggcaagataatgaaaaattgggacctgggagttatacatgggaatttgtttatcagttgggtgattag gagaggtggccttaaagtcctgttgtgttctaagagtctgtgattctgagtcttatttcccaacaaga gaggtacagagcagaagatgggattgggagaaataggataaagataccaggaaatcctaaaggtaaga aaaggaaggcagacctgaagctaactctatacttcaggtgcttgcctagagccagccctacctactta gagaatgttgaagagccagttaaaacatctttaacacggatgtaaaacaaaactatcaaaacctgaag atttcgaatgttctaacctactcgtcagttgggcttttttcacaaatacttcagtaaataggcataaa tttattttttaatgatagaaaatatctcttaaagaacttataactgtggataaaagcaccaccataaa aatcttgtggtgaaatatatatatatatatatatatatatatatatataaaattttaaatatggttag ctagaatatgacgacaatgtttatgaaacacagagactcttgacaagtcccatgtatacactataaaa ctttaagttatccactattcactcactaagcttatacttaatgagtgtctgctgtgtcacttattgcg gaaggcacaggcggtatagcattgcacaaaacatatgtggtctctgatggagtttttcagtctagtgg tgaaagcagtgaatgggtgtacagatgttaaataattgtacaattagttgcatgtgtaaacgtcaaag ttcagaagatgacaattgatctacggcaatgtttctcaatctctgacgttttgagccaaatacatctt tgttgtggtggactgccctgtccactataggatgtttggcatcacaactgacctctgcccattagatg ccaatagtactctcttctttaatcacaaatttgtcccagacatttccaaatgtcccttggggagcaaa atcatccctagttgaaaatcactggtctagggggaggtctttatgaggaagtaacatctaagaaagct ggtatgtttacatatagctacagtctattacacatgtatacatatgtaacaagcctgcatgttgtgca catgtaccctagaacttaaagtataataaaaaaaatgtaacaaaacaatacagtatgataagtgctat gggaccaaagatgaaagggttctactgcacagttatgaactcatagttaggcttttggggtcaaaatt ttgctgaagatatttgccacccacgtgacctttggcaggtgacttagcttattcatgcctcagtttta tccaatgtgaaatggggctggaaagtcccatgtacttcctaataactttgcggaaataatatgtggtt atataggaaaaaaaaaaaaatcctagaagtatgcctgctgcgtagtaaaaggaaggagaaggataaag agaaatctgcattttttcttctgtaatggggcagatagtaaatattttaagttttgtggcccaaatag tctctctcacatttacttgattctgcagttgtggcattggaagcagctatggacaatacttaaattag taggtgtgcctgtgctttcaataaaattttataaatacaaagtttgcaaaacaaagttgttttttttt tttttgtagtttgctgacaccctagtaaagaagcaccattgtcaacgttaaaaattatcaaattttta tttttcaaagttttcaaatttgctttgcttggtctagctcatgaaataagtcaaaagtagcaagacct ccacctctaaaataataatagtaatgataacctcaaaaggaaagaagaaatatttttaaagaagaaaa attattgttaaataggattattgtgcagagaaaacctaggagactcaattttaaaatctgtgaaataa ttttaaaaatactttatgaatagatacataatagcttttattcatattaatgactataaatgcaaatg gaaatatttcattcacactgatgacaatgtataaattaaggaggaataaaaattgtagaccctatagg tgaaaagcataaaaatatacataagaaaaagcaaaaattgactacgtaggattgttttaggatttaag atttattgtcattaaacttgcaataccagccaagttaacatttgaatttaatacagttataatcagaa tgcttttgatgtgtttgggggcaatataatttcaaaggaaataggcaatgatgtaatttaaagtttat atagaaggaaattgtgtgcgtgtatgtgtgtgtataaattggaaacaattttattaataagcatatta tggcagcaacatacacttccagatttctactatactttgaagtaattgtgatcaaaaccacagtgtgc tggcataaggctagagaaatgggttagtggtttacaagtgagagtccaggaaaacatccaaataagat tggatattttagttctgtgtggatagcctatttcacttaataaatagtgtctcgtaattgactattca tgtacctataagtttaactatagaccaaaaaaacgccctactagattaaggagctaactagaaatata aattcatataaacaataaaggaaagtgtaggactttataagcttcatgggagacagatttttggtaag tcaggaagcctggaagacttaaaacataaaattggcagactgaattaactgatagtttaaagcttcca tagagcaaaataaatcataaaccaagttttaaaatatataatggatttagagaaggtatttacaaaaa tatatgactaatggaggttaataataacaatatgtaagaaggatatgaaatggcattttactataaag gtcaaacaaatgacctataagcataataaatcatattaatctccactagtaataactacacacatcta cataatatagatgttacgcctgcatttgatttactttatctgtcttttggcagaactatttgtcacca gataaaaaattctatatcattaccagaaaggtatattattataatgtttattatgttgcagttgtaaa agaaataacagcttttcaattgtttacaaatcctatagaacatttactgaaatacatttacattttgt ggcaaacttggatttaaataccgtgttcgtgctttgttttatgccgttttcccatcttttctccagga atttgattgtgcttcattgaaagctaaaaagaaaaaaaaaataattctggttttggtttaaaaaatta ggttaggggttaaaaagttgtacgttgtcttctgtaaaaataaaaaacaagttttcttttgttcttgg 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aagacctcaggctgtttctcctttctaaccacttgccttttctaaccacttctcccaatttaagaaaa aaagccttatatttcatccaactctgatcttactaaggcttcaaacaaaagaagcatgaatgactttc atgacagggcaacatagctttttgcaagaagagtggttgctaactctttgctttcaactgaacccgaa gagaagacctgataagttgtcagccgatagatcattaaaaatacgttttggtaagcaatcatcatgta cttttagcatatgccatagcaggagcacaaatgattaagcaatgctactataatacaattccttccgt ttctttctactcacctatttgaataagatttttcatcatttacatctatacagacaaaaattagggat agaattgatgctgaagcctttccaattgtagaattaatttatattcttctgaaggtgtataaattgtt aaatacccatccatcttattaagagatgtattttcaataaaattttatttttatgtttatcaaatttt ataatatacatatattgttttggtcaattgcacgttaataattgtaacaatacctcaattgaaaaggt ttgttttttacatttaggacttacagtaacagaaaaaaaacactcattgtgtatacatactgtttaag aaaagtatactaggtgatcaataagattttttcaggcataaacatatatcttagttttaagatatcga tatttacaatctccctcaaattatattattttcagtcatttaagaatgaaaagtacatttcgaatgcg gattttaaatctgcaagggttgactcatttttcaagagtctttttaggggatacagaagcaagaatgt ttggagttccctgatcagtatctttaagagaaggtatttgttggtagttcctagcaaattccaacagc 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tctcaataataatcataatcataataataatttttaggaagcatcagaaatatataagaaaaagatta ttttcttaattgctttactaaaaacacctctatgatttttcagtaaaacttgattcttatgtcatgtg tgagtgtgatctgcctctcttgggatactactgtactcatgaggagtgatttttttctccaacgacct ctttgtcacgtcaacaggtcacaggaatagtgtaccctaaaaagccacctgccacatgctgctgaaaa tgtaaaagtacacacatacacacacacacacacacacacacacacacacacacacaccaaaatcaggt atcacaagctgaaaataaaattgagtccaatttttttttaattgagcagttaatgtccttaaaacaaa atcctatactgcaacaaatacttagccagatcattctgatacctccaaactgtggtgtattccaagat acctctatgatctttgatttgatccacagcttttcagttatcatgcaaataccttcaagttttatctc atttctcagtgcaaactcattaaaaattttcagctgaattcaattttataaacatgttgtgaatgtcc tctttatataagcaaggttgtaaggaactggccacataaacagaaaattgaataacatatggtttctg gccttagtgatctcatgtgtgagttaggcatatgggcaaaatcagaacactatagagtataagtctaa aatggtagtattttataatagaggatgaagagggtgctgtgggatcataggtgacagatataactccc gttgtgggacttgagaaaggcttcacagtctggaaacatttagttgctattgaacacaaaataagact cactgttgagagaagggagagggagggcatttcaatcaaattaagattctgtggcatattcggaaact 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ggggattatggggattataaggattacaattcaagatgagatttgggtggggacacaaagcccaaaca tatcattttgctcctggcccctcccaaatctcatgtccctttcacatttcaaaaccaatcatgccttg acaacagtactccaaagtattaattcatttcagcattaacccaaaagtccaagtccaaagtctcatct gagacaaggcaagtctgttctgcctgtgagcctgtaaaatcaaaagcaagttagttacttcctagata aaatggaagcacaggcactgggtaaatatacccattacaaatgggagaaattagccaaaatgaagggg ctacaggccccaagccagtccaaaatctatcagggcagtcaaatcttacagctctgaagttgtctcct ttgactccatttctcacatccaggtaacactgatgcaagaggtgggttcccatggtcttggtaagctc cacccctgtgggtttgcagggtagagcccctctcctggctgcttttacaggctggcattgagtgtctg cagcttttccaggcacgtggtgcaagctgttgatcgctctaccattgtggggtctggtggacagtggc cctcttctcatagctccgctaggcagtgccccagtggggactctgtgttggggctccaaccccacatt tcccttccacactgtcctagccgaggttctccatgaggtcttcattcctgcagcagacttctgcctgg acatccaggagtttccatacatcctctgaaatctaggcagaggttcccaaacttcaattcttgaattc tgtgtatccacagactcaacaccacgtggcagttgccaaagcttgggacttgctccctctgaagcaat ggtccgaactgtaccttggccccttttatccatggctggagtggctgggacacaaggcaccaagtcct 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ttgcaaaagtattaagaaagatcatgagtacccttcactcatcttcagctaatggttacatcttacat aattatatgtaatatcaaagccaggaaaccaggaaattgatgttgatacaatctatgctttattcaga tctcacatcttacatagctatgcacaatataaaaaccaggaaattgatattaacacaatctatgcctt attcagatctcaccagcttttacatgcacttatctgtgtctgtcattctatgcaattttataccatgt ttagagtcatataacaactacccctattttgatacatggtactgaatagttccagcgtcacaaaggaa ctatctcaagccaccctttaattgtcacacccatccaatctcccattctacttcctgaatcactagca acccctaatctgttctccatctctatgattttgtcttttcaagggagttttctaagtaaactcatttg gggaaagaaaggagatgaattgttctagccacggagtggagaacagagagtaagagtacctattgaag cagagggagtcattgcaataattcaaatgagaaataatggtgattctaaaccaggaagctttcagtga aaacaatgagaggtacatggattctgggtatttttggaaggtagcactaccaggtttgctgatgaatg gggtatggggtgggaaagaaagagaagagcccaggatgagtccaaggtggataaggtgaatagaattg agaaaatggtagaaggatcaagttagatggtagaggggtaaaggtggaagcaataattttgttttgga attgttaggtttgaaatcttgttagacatcccagtaaagtcacaaagagtgcagttggatgaaagtat gggattcagggaagaagtatgtgctagagatgcagatttgagagtcatctgtgtggaggtattattca aattcaagtccccttggaatgaatggctattcaggcagggtcttcataaaaatgcttgttgcatgcct gtaatcccagcactttgggagtctgaggtgggtcgaacacttgaggtcaggagtttgagaccagcctg atcaacttggtgaacccccatctctactaaaaatacaaaaaaaaaaaaagttagctgggcgttgtggc acatgcctgtaatcccaggtacttgggaggctgaggcaggagaattgagccaagattgtgccattgca ttccagcctgggcaacaagagcaaaactccgcctcaaaaaaaaaaaaaaaaaaaaaaaaaagcttgtt gcttcaaattcatgtcagtctgtaaaattatctgggaaggcagtacaaaaactgtcactttgactacg atgtttctggtgacccatcttcattgatcagtatggaaaaggcatgtctctgaaaatctctgagagtc tttgatacagcaagaacataaggataaatcattcttctatgttcatggttgtagaggatcttgaatgt ttaatggcagaatagccagatcacactctggcacttctgtatgagaggctgagggatgttactgattc accccgagaaatatttactactaaggggacagaggcaaaggggatacaagacttcaccctgagctgta gcgctccctccttccctatcctgctttcattcttcacattgttttccttctttcttttttattattat actttaagttctgggatacacgtgcagaatgtacaggtttgttacataggtatacatttgccacggtg gtttgctgcacccatcaacccgtcatctaggttttaagccccacatgcattaggtatttgtcctaatg ctctccctcaccttttccctgtgtccacattgttttctttctttttgaagcctctcattcactaggtt tcaatcctgccttgctagtgttctaactctaaggcctaggcaagttatttcaccgaacttagcctcag tgtcctcatctgcaaaatggatagttttatgatatcttcagcccttaaagtcaatggttctgacagct agggtgtactatcttcttggatatcagtcatctcaagcaagccctccttttttggaccttcttttcac acacttcacataccttagagaacataatacacatcctctttactcagggcttattctttataacaggc ttcctaattcaattaactcaacttttcaaaaatattagtgactactgtgatgtaaataaatttgcatt ttataggggtcttagtaacccagaagggagtggggaaaattaatatatattgagagtttattaagtgc taggtactgtaaatattttcttgtatttaatcctccgagtaattctacaacaaagatattatcattgc tattatgtaaataaaagaacaaagtagaaagaaacccacggtcttgtataagctcccctagttggtgg gtattgaagggagtatttcaatctttggtagcttctgagtttttgttctctcagggaatctgccagat gtccagggcacctgccaaaccctatgaggctataagaaaaccattaagggtcttagattacccagctt tttgggagttagaattctgaatgaaatttagtgttcctgcagctacaaaggaattgagttagggaagt gatgactttatctttagctacattggttattttccttataataatcctggcttggtagattagaggca gcccgagtaacccagaatcgctaaaatagaagtgcgagctcattgcccgctgtccttcactatgtttg catataggaagcaagaataaaacaagcataaaataggctaactagcttgtcagagctcttcacaccaa gtctttgtgagttccaataagacactgactattattaaaaagacagagactccacataagtaggaatt tattgttttccttttcagtcaccaaaggacaatcctctgcataggttagcaaaaaatggtactgatcc tataatctctaatattaaagtttagatttggcaagctgtacatcttatgttgttcattaacaaaaaac aatattgattggtatcttgtactataacttgtactgtgggtcaaattccaatacagcaaataccattg caataacaattctacaaaactacatcaaaaaaacctttcatgtttgagccaacagcctgatagtgcta aggactttgagtacagtatgctagaagattcttaacagttatttgtcctggacaacaaaggttgactc cattaaaaacatagccatcagtgtgggattatttccaaatcaagcttttggaaaagtcaaatgaaagt ttgcaagcaggtggggcatggtggttcatgcctgtaatctcagcactttgggatgctgaggcaggcgg atcacctgaggtcaggagttcgagaccagcctggccaacgtggtaaaacccccatctctactaaaaat acaaaaattagctggcttttgtggtgcatgcttgtaatcccagctactcaggagcctgaggcacgaga atcacttgaactcgggaggcagaggttgcagtgagccgggatcatgccactgcactccagcccacatg acagagtgagaccctgtcttcaaaaaagcaaaaaacaaacacgcaaacaaaaaaaaaaaaaaccaaag ttggaatgcaataaatgttcattgaatgaatactgaatagggagtttcagctaatccactcaaaatag tgctgaatttccagctctaaggtcaatgcttggcatatatatcctgaaggaatgaatggacacagagt aattttttttctaaaatgcaaattcaattatgtcacttcccttcttaaaatccttcagtagcttcccg tagcctccagcatattattttgaatagtgcttctcaaactttgatgtgcatcagaatcacctggggat tttcttaattaactgatgctgattcagtaggtctggggtattgtctgagattctgcatttctagcaag tgctcagggttatagcaatgattttggcctgcagaccatactttgggtagcaaagacataagccactt aacttgacataaaagactgtttagacccttagtttctctctcgctctttccccattttgagcttttgc tccggttcatgtttttccctgaaaataccgtgatcttacattgtctgtctggatgctgaattttccct aattctgggcctccatgtagttttaggtttgacatcacaaccaccaaaagatttccccttctccctta atcttggttaatgtcactctcatgtattatactgttaatgaagcattgaggacataaaacttatcaaa tattttatcacaatcaatgatggcaccagtgataacatccaaatgcctgggtgagtaaataagaggag aataggggacttgttgttaaactaagtttgcagagaaaaaatgtactgattataattaaattggatgt ttatttgttatgacaaaaaaggagctagagtcttttaatccaccccttggcaccactgcttatctcct tgtaacatacgtttgattcccatgtctatttcttccatatgggaaatttcagctccctaaacatcacc aatacaacctgttgataagacaaagttaaatttattgcttactatggtaagaaagaccacagcctgga caaagctttggtagtatttcataaggagaaaggtgaggttggatttcattgggagtatgaagcttggt ttaagattggtctttcactgtgggggcacaattaggattgggtaaggatcatggtattacaacttagt ttggtggaaacagcacagtgaagatttctagccaagaggctcagagactattaaggtgtgaactctat tgatgttttttgttgaagagttgatgggagtttggggaagttactttagtgaacagtcaaattatttg cctggccaagagttatctgtaataggaaagttatgctaatgaagacaatggaaaggtaaaccatgtta atgtcgacagccagctatgtgagcataaggggtaggtagctttggtcctccatgtccaaactgtttgt agtggtaagtgatcttcattctcacatagattgaaagcttcctgaggacagggcaatgtctttgtaaa ctttaaaatatctatgtcctgcacatcacctgccgtagacaagcatctagtaattgacggttgggtag atactgagggaaaacatgcaccaaataaaaatggcaataggacacaaattcactatcatttggaagaa taacagtgttttccactgatatttgctacacacagtggggtccacagagcagcagtaccacttgggag cttattggaaatggagactctcaggcaccaccgcaggtccaatgaattaaactctgctttttttaagg tcatttgtattcaattattatttttttcttttttctttactttcgatgcatttttctttatttgtttt tgagatggggtcttgctattttgccgagtctggtcacaaactcctgagctcaaatgatcctcccacct cagcctcctaagtagctgggatcacagatgtgagccaccacacctggcttgtatcacattaaattttg aggagcagtgctttaatatctattccattctcatcacttgatgaggtattattaattccacttatgga tgtggaagttgaagccagaaagtttaaatgacttgtacaaggtcaaacagcttacaggtagttgagcc aagaggctctcaagtcttctgcctccacaaacccctgttcagctgctgccctacaatggaataaaata tactaatcccagagggacaaatatgctaaaaatctcaatattatacactttggaaggtgcaggtgcat tatctttcaattctaatttctctttcaagttttetgatgcataaaaatatgaacagcaggtctgagca atgtttagatgccgtgctttgatccttttgccattcaagatgtttgatttgcattctgccaaggaatg tctggtaacctccatgatgcagaccacaccattagtcaagagagagctgacgtaccttcatctgagag ctggctggctgtgagctgctcagagggaaaggatttctatttacaaattgtatcgattatttataaat aaaagttccccttgctttcttcagttgtaaaatctgcagttagagagtcgggaagaagatcaaaactg catacatttgcatctgccaagcctgataactagttccagaattacagaaatggtgctgaaatagcacc tcaagtaccaggctctatcaaatttaatctatccataaggcaactgccaattatattttagagaaaaa atgtagactgaaaagatagacaatccaagtagcaactcctgtaaaattatatgcccataggagcaatc ttgaagatataaatattggtatgtttctccttcatttatcatttatctgatcatttgacaagtattta ttgaatgcctgttaagggtgtagatatatgtggtgaggctgcaggtgtaagtaggtctttctgaggat atgcatgaagttgatgttcataacttggagatgtgtgtatacagactgaggattccttcagtggatat taagaagtggagtaataggcagtaaagaatacactagtcagttgtggtacataaacacgtcagcacca cttaggtattaacttcctgttttgttttgtgtgtgcttaattacgctgtttattaaacaagcacatca taatctgcagatattgtcataaacagcacaataaagcctgccacatcagaatgtcatctatcaaatta ggtgtgttcctcagctgtcccgataggcacacacctgtgcctgtaaataggcgcttggcggagattgc ttccaggtgtggatctgttgggcgaccttgggatgtagggcactttggaaccttttcctctagcttca ggaattaacctctgggcttggttccatgccagcttgcattttgctttgggacagtaacatgtaaagaa tatgcctgtgaatttagggttactgagaagtcctcatagaagaagtaaaatttccttgaggaatggga gtcttttattcaatccaggtttaatgcaaggcttggtgaacagctccagaaggttaataattgcgtgc gtgtgtgtgtgtgtgtgtgtgtgtatgtgtgtgtgtatccttttgtcattcaaaagtatacgtataca cacacacctgtacagctgatgataaatatacattgtatcaatgagttcaaatgaagtgtgctattcat tcactgaggaatgggctattataatgaactattatgatattagaaattgtcagggcaataagcaaata atacatacggttttcaacaaactttctaagtattgttatcagtgggtttgcttaaatctttttttaca aatttatttatttttttgagacgaagtctcgctctgtcgccaggctggagtgcagtggtgcaatctcg gctcactgcaaccactgcctcccgggttcaaaagattctcctacctcagcctcccgagtagctgagat tacaggtgtgcgtcaccatgcccatctaatttttgtatttttagtagagacgggttttcaccatgttg gccaggacagtctcgatctcttgaccttgtgatccatctgcctcagcctcccaaagtgctgggtttac aggcgtgagccaccgtgcccaggcaatagccccattgctcagtgaatgaatagcacactttattttaa ctcattgatataatgtatatttatcatcagctatacaggtgtgtgtgtgtgtgtgtgtgtgtgtgtgt gtgtgtgtgtgtgttgaatgacaaaaggatacacacacacactcttattaaccctctggagctgttca gcaaaccttgcattttttactttcattacagtgtgtaaataatttagcaaattctaatttgaacctga tatcaattgagcatttaatatttagccaaatatttatcaagtgctgactgtgttctagatgctggggc tgcaatttcgaaacagaccattgaggccctcatggagctcacaataaatgatcttccttaaagtatca ggtctctggtttgttaccgtattttttaaattgttaaggaaagaaaaaggccctatctttttgtagac aaacatgccctaagtgcttccagaaataatctccatcaggtaatgcagactgtgtgtggagtgaaatt gagtccaatccatgatccagcagagtttcagcccaggatttctttagagcctttgctacacacaaagt tggctgatgtgccattcagcatcccagcagctctttctcttcacactagcaatggcaaagctttgtgc ggaggcattgctggctgctctgaactaaaagcatccgtggggaccgaaagaggtttttgcacacctta ttaaggtaggcaagtgtgtctgagtgtgtgtgtgcctaaaagctggaagacatctgttgagaggaaag tgctcttctgtgggtctggcagcttttctgtaagtcttctattctgatgcaggagcgtgtgagcagtg ggtgggaggagatgctttggtacttggaatgctgaggtccggattaagtggtattgtaatagctagtt agaggcagaataaaaagctgggaatcaaagcatttaaaaatgcatccttccattatttgctctcaagt taaaccatattcattctaggggaaattaaaaaaaaaaaaaaaacacagcaagggcaagtagcccaaat ctgtaaggtctttgagcttctctgttcgtccagcttttgaagtcttcctacagccaatttgtttggct cctctggagggggcaattcatatccacttccctctcctggagcatttctttcttctatactccatcag ggaacaatagagtttaacagtaacaggcaattttttttttttttcaaagcttgtgccctcttctgcgt ttaaaggtgttttttaagagactcctgctaggggaatcttggcgcctgtgtgttaagacggcaattaa cttttagtatcagtgcttacattaaattttctctctttctgctttactaaagcagtcattaaaattca gtgtgagtaccatgaaactttatcataaaaccctgctttgcttagagaaccttgattgttttctgaaa gcagccttctcagtttatatatacatagctgccttccttggaatatcaaattgctttgtgtcacatta agaaacactaggttgaacctctatactgtgttttatctgagaaaaatactactgcaaaaagtttgatt tgttcaagttttaggatgaaaatttctttgtaacaagttatttgagttgcatactatgtcatcgtata tctctttagttcaagtaattttgcaattaacatacggttatgtaaagaagataatgatttatttttta tttatatttttaaaagttattaagtgaggttttcctttcagtaagagtttagaaaaaatagccagaac aagtaactggacttggaagataaagatacctttgcacttctaaattttacctttgtacacttcggttg tgatttaatcattgaaatgcctctgctttgaagtaaatgcatcacttatggtgtatgctgtgttttaa taaagggaaaacagttatgggttctctgttgcacatttgaatgttgttattttttgctgtatttaata acctcttttttctcttgtgaggtttactttggaaatgaggcatgttcaaaaataggctgacattcagc ttctatgttttaaatttaaatgctgtctgtgttttatcacatctggaatgtgtggggagaaaagatac caagttttattatttagatttaattgtagaattgcagattgatatttttcaatgcattttcattatag tttctgccatggaggcagcgtgagggctttcaggaagatggagtggtgtaattaccaggtgcgcacgt tcattaatccttcctggctagagaaagcttcaagttcttctccagtggcccattcgtaaagctataaa tatctaaattgtgtcagccaagaagtcacacagaatggtggctctttttgagttcaatttcatgcact gttgctttggtcttgtgaggaaagctctgaattccttaggatagtcttggttgtgaagttccaaaaac aaaatatcaaatcattaaggatttaatttaaaatacatactcttctttcacaaactagatgattgcag taatgtggattataaatttttttttttgctttatttctttagagctcctctttttattttgtatgatc aagattatagctgagattttggtgatttttttaaaaagatttatggcttatggtccatcagtctctcc actacttcaaacctgtgtacccctgtatattatctgcagtactggaatgtttgcattgtatgtggaag ctatatacgatttggtaaaaaataacacttaaaggtcttcgctaagagtgcttatttaatcattaaat atcccttaataaaaataattccagagatattgtctgtgtacaaacttaaaaaaagagaaatataaaat actgtgatgtgaataaaatgtatagcaatacactccaataataccattcttatgttttcccttgttct caactgaaataactaagctaatagagacgtcagtaaggaatgtgttgtttcttcataatacaactaca aactcatctgataagaacaacctgagagtgaacgttaactttcctcattagaaagattcaatttaaca catatatacaaatacatttttaagataatgatatttgcagagtttttgtattctatggagtaaaggag aattatcacatattcaaagtaaaggtataaaatacatcttaatgttttacttaaattttaaagggtcc aaaatatactaaaattctttttctaattctttcctatgtttaaacgtgccagagtcattggaaatagg acattctttttcttaagaagattttgcccaaaatatttaaaactattttcttttcccttgattttaca atttcaatattcatggatttttctactttaaaaataacagtagtttttatgatcttaaaacaaatgtt taagggcactttcgctctctggagactataccatccacatatttattatcagcaaaagaaagggcagg gcatacttttatttgaagttgagtataaaaatgtgtctgtgtgtgagtgttattaaaaagataagtga agagacaaatatagaatccaggaacattttcagcctggcttttactctctctaaaaatctaatgaaac ccttgagcatctcttatctcaaggtacattaggaactgtccaacactatgatccgatgggagatcagt atattcatataaagaagaaaatttgttgttagtgaaagtcaagtcttttaaaaaaataatagttacag catttgcaatatacaagcataatagatttactcaacgcccaccccccatctttaaaaaatcaatttcc gacagttgtctactttaaaattgaacatatttgctacctggagggaacattgtaatgtagcccatatg tggtatgcatcctgaagaaaacctgaaattatagaggaagttatcctgccttctttcttctgttgaat gagttaaaatatattaacaatttgcctttcactttgtatttatcattttgtatctttgcatatttaca tatacattcatgtgtacaagggcatatatactcacaggtcagggctatttaaacagctatttatttga atatgccagggaaaatctccaagatataaagaagcagttattagatactatgtcagtatagaattaac agccatcttttttaagatggaagagaaaattaattaattacatacaatttctaacctcaagacatttt ctttctggagacaaggaatactgaggtgctcacgatagtgaagactcaacaagaccctaataaaatag atgaggataagtaaaactacaatagccaataaaaaacaaaaaacaataaaccatgtttcgctggcatg ttggtgagtatctctgtaatatctgtcaataagggtctctgtagatttggagtaatgttcaggaacta cctgtactagagaagacagtggagaggactccagtggctaaattctgctgcctttgcttccagaaatg taaataataaggaggtattgtggcatttcctggaagcagtagtcttgtttcatggtctgactgtataa gaatgcctagagaaacataacctcagctgactaaactcccttgatgattgtcactttgtcactgaact ctgaccataccttttgcctccagaggcaaaagacgggtgaggaagtgatctcctcatctggtttttaa acaagtatataactagagaactggattatctcctaaacccactcttgtccctggaaaaaggggagtca tcctatccgtttcttagccaatttatgtatactcttagtttgagagcatgagaaggaaaactattttc ttttcttaccttggctgggtttttaagaatttatttttagtttaatcaaaataatattttaaaaggta gtaagcctctcataagcagtttgatctgttctaaaataacttcaatttttctttttttaaactttctt ttatcttacacacaaagtataatagtaatatgtactcactagaacaaatgaaacaggatggagtcaca tagagaaatatatcatattctccctatcccctcccttaatattaacatttaggtgtcatgtgcttctc cattaattttcattgcaaaggcctaaattttcttccaagagtgaggagtagcagcacggtagtttgga cctgatatagctctctttccctagccttttgcttaagtgctttcctaggggctgactttacttaccta aagatgtttcaagcaagggctcacatttttggtagcagaagacacttactgattgctctcactaataa ttttgaaaggaatgtcaaaatctgggaggatcatgaaagaaatatcagaaatttcctttcagctgcca ttctccttaatactgttatcaataaattcagcatctcatatgtgatagcaaaaaaggtgctgcctttt gttcttgcatcctgaggttcttacctaataccatggtagcaataaagatggtgagaaaattgcttctt ctatggtgttcaggtcctgaacgagcaccctcacctccacagacggtggcaggtattcaagcatttta cagactttggagttaaatatagcagtgttattctaatttaggtatgccaccaccagcggcaccggcaa ctgcaataggaaaaatgattggcaatgccagctatctgatgttttcatgtgccaggtgctgtcagttc ttcacagtattacattccatcctcacaacaagagagtgccagtgagtgttgctgtgtgccagtgccca ggctaagggctttgaacacattaccctgttttatcctcataactttccacgttatttttattcctgaa tgaagaaacaagttctctgtagagatgctgtcattgatccactcatatcctttcacatccgtttaaca ttttccctgctgtgcttttactcccaacaactagctccctaatcgctctgttggagggtggccttgag gctgccagagcctatttggtctgtgtaaagagagagatggatctatcctggaatttatgtccctgtgt gtgggaagcccttaatcaatgactgctggttgcagacacataaatacgtgagctttcttgttcccaac tgagaaattcagaagtgtgaatggcactgccaccctgggcttttatgccatatatgtgtttggtctgt ttcccttcccaatctcacttcattttcccttaccagtgtttcttgaaaacacatcccattagatcatt tttgcatgaagcttcatctcagaacctccatttagggaacccaaactaagatattctctaaaatagaa actttattgataaagtttccaaactgtcttagtagatggccaatataagaccaagccaaatctttctg ggtccaaattccctgtctttaattaatagactccattacaacacattcttcaatctttagtcagcaaa cacttaccacgtgcctattttatggcatattatatttataccatagttaggatattatggttcatgaa tattttatatctgtacacctgaaattctattgacctctctgggccacagttttgcatctgtaaaatca gcacaataatgctacttatctcatagagtagacttaaaaacgaatgaaatgatatatgccaagtgttg agaatcacaattggcaattactcatgctcattaaatattagctgtttttatgagtattgtttcatttt cggtgcataatatcctatgcaaagaacaaaaggtattggtataggcattgaaacttgaagcatagaag aaaaagttaattaaccggtgccccactagatgcctctaactgctggctccgtgtatccctttagcctt ggctcgtcacgagaaaaccttggagacatttctgctggactcagcagatcaatttaagaaagatgaat gacatttttcttgaaatgtattcagtcatagctgcctttttctactttcatattttggagttcttaga aaaaattaaggactcctttttttaaagaaaatggtataaaagaaaatgcatatcactttgtcacttta ttattgtaacctcatcaaagtattcagtgtaaagacagtagccaagtgaactcttcttgtaatgctcg gaaaccattttagcaatggtaaaattgctgcaatttatattcgtcaaattgcatgatttgacttattt tagaaaagttattaacttctgaagagaatgcttcagaagcatttaaatgagtacaagttatcaccagt gatatacataaatttcatttcaaaatatacttctagaaactgtacttagttagctatagtatttgtac aaggattaattcctatttcattttgtaggaatttatttatgaatgtctatggcctgccagtgtaaagc agacttagagcatcatcttttacaataatctttttttttttaatcaaaggggagatattctggtaaaa caaaacaaaacaaaaacaatagtttattctgcatttttattaagtccctctgtaagtcatccctgaaa tgggatatgtagagtcttatatttatttatttctcagaagcttattggaggtgatatgaaggatttta agaccctactaactaacaaaacaacaatttaaaattaattttcaaaataccttaacaaatcttattct ccttattttcaaattctttaacaatgtttttcttattactaacataatatcttctgatgtagtcataa taatatctaaaatgacaggtctaagtaacttacatggattaattgagtcttctaaatagtaaggtaga tggcactattacttctatatgagaaatgaggaagtagaggtataaataagaaattttttggccgggtg cggtggctcacgcctgtaatcccagcactttgggaggccgaggcgggctgatcacgaggtcaggagat cgagaccatcctggcgaacacggtgaaaccccgtctctactaaaaatataaaaaattagcctggcgtg gtagtgggtgcctgtagtcccagctactcgggaggctgaggcaggagaatggcgtgaacccgggaggt ggaggttgcagtgagccgagatcgcgccactgcactccagcctgggtgacagagcgagactccatctc aaaaaaaaaaaaaaaaaagaagaaatttttttgagtgtatacagttagaaaatggcaaaatgggaatt cagacccaaacagtaagactcaaggatacctttcttatcagtatgctaatatgaaaacctaagcatac tagaaaatctaagtgccagttggaaaccagaattaacattttggtgtgtaactttctggctgcttttt ctatgctaacaaacatatatgacatacaaaaatacacacatacacaaattcctgttcactacttcttt tatgttaacatcacaatgtaccgtacacagctgtattattttatatttgatttcatattttttctaaa gtcagtgtatttgtcaaatatcaacttatctatttaataggaatatgggatgatctttgcttatacat acatacatatctatataaaaacaaaatcaagtattttaagcgttcaccagaagtcatatgtcaatcag taaagtatataattttttgctgccaatgacatatatcataaaaacgctacctatcatagaatgaaaat gaaacacagcaatattgggacacctattctcaagcaacagctttgtgatttattagctatctcacatg aaataactcattaacttggtattccaagcagcaaaagaaggatcacttaggtcacttgcaaaataata caaagctaggtttaggggtgggttgcgcttggtgggatgtagatgaaaccatatgggcccttgagttt ataattgctgggatctgcatggtgggtatatggatgtttattacagtatgctagtgagttaagaaaga agaggaattattattgacttacatcatagagtttatgcaaaaattaaacgataatttatttttaaact ctagaggtataggtaccatcatgaagggacccacagaactgatgtagccagtaattattggagctgga acagatactctgctgtcagttgttctggttttgtggtcattgttcttgcctttgcaagttaccaactc taagaccttgggcaatactttaagtcttggttgtctcatctgtaaaatggggagagcagtaagtgtct taaaggtttattctcatgttatatgacttacggtatgtaaaacatctgcgtttagacacatagagggt gcttaatggatgattgctctcattattaggctacatctaatctatgaatttaaaaactgtatagaaat atgtgacagattctttaagagccaaataccaactacagtgaaaaatacttaacacttgctgagctctt agtatgtgtcaggcttaactaccttaatgctcatagcaatcctataagataggtactcttgttatcct attttatatcttctaaaattgaagcaagggaagttaaataataggacaaagatcatacgctatctatc catatatacccatctggctgtctacctgtctccttccatccatccatccacttattcatctacccatc catccactcagttacttctctctctcccaccatccctttccctttccctctccctctccctgtctctg tcactctcctttacttatctatctatcgatggatcggtttatctatcatctatctatctctatcatct atgtatagttgttaataacactaacattttataaattacaagactgaaaaatgttttcattaacttat ggtaacaaaagaccacattgtgaataaaaaaagcagtaaacacaggtctctgcacatatgaaagagat gtcctaaacaggaagagatgtcctaaacagtagggatacatagtatcatacaatcaaaacatggcagc cctataaaacttacaaagcaatttcatgtaagttatttcatttgactcttaccacaatctatgaggtt actatttttatttttctcattttacaggttaaatttaatatggcttccaataaaaaattagtatggtt aataaa£atcttgacgtcttgctcctataatcctaccgatagtttacagtaattagtaaaataaaata ataggaaaaatacctttgatactagtattaaattataatcatatcattaggtaatttcaatttgtgat tttcaagaatctgtaatatggtagcttcttcctactgacatgtttgaattcattttaaggcttataat tcacaagtaatctatatattatctaaaatgtaaatgcacattcacatggagataataaattagcgtga aatggctgtattttgctctctataatttttaacatacaggaaatcactgttgtctcaaaaatcaagga aatatagtatttgaggtgaacttattctttctactattaacacattttaatatagttctctcacagtg caacagagcaagaagctttcagacacatttgctgctgcaaggagcatgctgtgctgaacttaaaacac cttccctttcaaactccttgggactgtttttttccaagagacttcaaatgcactaaatttagcatccg ttggaggcacacccaggcatattatagtgaaagccccaataactgaatgtgttaccactattcacaat gtttatgtgtgtatatgccttatctatgatgtattgcaaattacaaaaattgtgttattattcacagt aacaaaaacacttccagcaaatttctaacagtgatctcttttgaaataacttacatacatgtgtcatg ggtcttaaactttgtcacttttatgtttccatcatgttgttttagccagtgagggttttgtttggttt tcatttatgattatatactttcaaaaaatagatttcaaagtgtgaatttgattgattgattgactgat tcattgagacggtgtttcactcttgttgcccaggctggggtgcaatggtgcgatctcggctcaccaca acctctaccacccaggttcaagcgattctcctgcctcagcctccctagtagctgggattacagatgtg caccaccacgcctggctaattttttgtatttttagtagagacaggggttcaccatgttggccaggctg gtctcgaactcctgacctcaggtgatccaccctcctcagcttcccaaagcactggaattccagacgtg agccaccgcgcccagcccgtgaattttatttttgaaagacaagaatgtccttgcctaattgcataata gtttaacatcatgaagactaaatatgctttttagccatgacaattttatttattattgttttcatttt taattttctcaaagatcctcatcagtgtactctttttggtcttccttataagcgtattttaacaggac ataataataagataaatcccaactttttaaagttgtatccgtatgtattactttaaagtgctattaat ataaacgaattagaggcaacttttattcaatcagattttaagtaattttaccaaaaatatggccttga taatgtctctgtaacaggttctctgtaatatacatgctgaggattggtttgtctttgcttttgatact attttaattagaaaagtaatggggaatccagacccttctcatttaataatccagagaaaaatcagtcc atgttctaatagtttaaatttttctactaaaacccatgtgagaatccatatgagtggaatggagagga gttcagcttcaaagttggcagatttgagatgattctatggcaacagaaatgtgcttgagggaaatcag ttgcggcatcttctataattgtgtcacctagattttgccttaggaatttctagatttccatagaacat tgtgacctcaaatgctttatcttaataaagaaataaaagcagattagaagaattatttgcctacagtt tgtgggagatgggcaagtcttaagagtttattaggtacccagaacgaaacatattttcttgggcctca taatcacattgaaatacaaggatttagttatacacagtgaccagttagtgaatgacagtcttcagtat ctagtagacagtaaacatataaagatgtatttgtggccgggcacggtggctcacgcctgtaatcccag cactttgggaggccgaggcgggcggatcacgaggtcaggagaccgagaccatcctggctaacacggtg aaacctcgtctctactaaaaaatacaaaaaaaaaaaaattagccatgcgtggtggcgggcgcctgtgg tcccagctactcgggaggttaaggcaggagaatggcgtgaacccgggaggcggagcttgcagtgagca gaggtcaggccactgcactccagcctgggcgacagagggagactccatctcaaaaagaaaaaaaaaaa aaatgtatttttacttttaactacagcgagagaccctggcagcctacagcatacaattagtgttcatt atttagattgcatggatttaatgtgaggggtcaattacttgtctaaccagtgagcctagcctcttgct caatactgcctgcttcatgagggtgaactgtgctggagaaatatattacaggattatctgcagatttt ttttaaatgagtggttaagtcaaaagttcttgtgaaaattcagagtaataaattattatgaagttgtg taactaggtaaaggatagtttcttttacacgggtaaagattaacatgaggaggaaaactttagcaatg gcatttaattccattcaatatatttatattgagctcctttaaaaatacagggccttgtggtgggtgct gaggacagaacaaaaaccaagtaatacatgaacataacccttgatttcatgatctagtagacctataa aagttgtcgatatctgatgaaaagaaaatggtaaagatattccaaacagtgtatgcaaatccagagat aggatggaggggctctacctgaaggatgatgataagaaaaccgtgttgagtgaagggtgatttgtgga attcagataaaatatcagtcttgaatgctgagtgaatactcaatgattgactagatcccatggacagt aatttcttcaattatgacgatgctagtgtttatgactataactatcattctccatgccaggcactttg ccatttggtaaatgtatagtgtgctattctaacaagcatgcacagagcttttactttaatgtatccat gagtttattggggttcagaatttaggtaagctttgcaaggtcgtagcatggagtaaaatatctgaaat tcagacccatatctaactaagttcaaagactgtacagatatttctcctcctttgtgcagagaaggata ggaatgcttccatattatcatggacttagtcagatgttttaaaattataatgtcctgtgttaatgaag aagggatgatattcagtgcatattcttaaccgttactttgcttaatgctctcgacttttctgtgagat ggatagtgtagataaaatccccaaggggactcagcaagtgcaagtaaaacaatgaaactttaaagccc tttgtcaaaacctctctttttctcagaggatggaagggccgtaaaggttggtgaggaaggatggacca tttcctatgtagtcttctgacaatattcaaacaaaaggagagtcagcaaatcccccttgatgtgggaa gttttaatacaatttgcagagtgtctctctggagtagacatcctcctctgcaatcgtgtcttctatat agcctcagggctttgggtaggtaatcctctccaaggagagtcctggagagggctgtctaccccccttg caccatcctctaacattattctatagctcagctccttgtttctgtttcctgccttgtttttgtctgag tctgcaattatgatgtaagcaccatgaaggaaggtatgttgccagtgtttgcatcagcatatcccccg tgtgtagcagcgcaagggatatagtgagccctcaatgtctatttgtagaaaaaagaatgaacgtatca acgaaatctgatacatattcattgtgtctgttatctccatctctcttgtcctgccttgttatcttgcc attttcacaaaaggccccaaggcccatcatttcttgtgtaacttccagagtgttaatttttaaattaa aattaaggctttctacatgagtgtctattatttgagaaaccatgcaagatcgtgtgtgtgtgtgtgtg tgtgtgtgtgtgtgtgtgtgtgtgtgtgttgcactctatattatattgaattctggattttttcttat aaataaaattttaaaaatagttctttaaaaataggaataagatgttttaggaggcacagagagcaaag gagaataaaaattgcaggtttggggttgtgcatactaattgccattgagtaaagagagcacactgagg ccatttagaagagaattaacgtgttttgtttttgtttttgtttttgtttttgtttttgtttttgtttt gagacggagtctcgctctgtcacccaggctgaagtgcagtggtatgatctcggctcactgcaacctcc acctcccgggttcaagtgattcttgtgcctcggcctcccaagcagctgggattagaggcgcccacaac cacgccaggctatttgttttttttttttgtatttttagtagagacggggtttcaccatgttggccagg ctggtctcgaactcctagcctcaagtcatccacccgactcagcctcccaaagtgttgggattataggt gtgatccactgcacctgaccttatttttattcatttaaaaatattaaatgttactgcatagggagtaa tgggcttaacaatgaggtgaccaaaactcctatgtaccatgcagagcaatgtatcaaatgtttttaac tataaacttctcaaaaacataaacctaattgttctgcagctgcaggttatatctgccttgtttgagca aaatttggtggtgaaaatgccttgcttccatttttccttcaataactgatatggtttggctgtgtccc cacccaaatctcatcttgaattctactcccataattcctacttgttgtgggagggatccagtgggagg tcatttgaatcatgggggcggtttcccccatactgttctcatggtactgaataagtctcacgagatct gttggttttatcaggggtttctgctcttgcgtctccacattttctcttctgcttccatgtaagaagtg cctttcacctcccaccatgattctgaggcctccccagtcatgtggaactataagttcaattaaactac tttttcttcccagtctcaagtatgtctttatcacagcatgaaaacggactaatacaataacctatata attttgaaaagtacttgtctaatagactttcacaatagaaactatatccttatcaactttgaaaagtc attgcttaatgcctttggataactgaattttctaagattattttaatttcgaaagttaaattttatcc cagtgttgacgatttttgtatgctacttttaaaatattttgtcagtgatttatatctatggtgcaatc ttgtaaaaaattaacaatgcaaatgtggctagaccatttaaaaatcaatatgttataattcagcccat ttaatcactttagttaaacatcttaggaacaactcagttccatttgagagaagacacagttttctaga tgtgtgttgtggcatcatattgctttacaatatcttacataaggtgaattcaaatcatatcattgaat ctgttttaaattctgtcatagcttaagattagtgactaaatattggcaggtttatggaagtaggatgt aaacaagacaaaaacaagggtggaacaagtaattttagtatattattcacttgcacagagaaaagtca ttcacaccttcttcagctttgtgaagaaaatagactaaaatcctgttgatatagcaactatgttttcc gtttcttgtataaaaataaagaaaacttcctattaggaattagccagacattttaattttctctcttc tttctctattttcccttacagtctctttgaaggcaggcaaaatttctataaagttttaagaatgtttt aagatttttttattgtgaaatattcatagactcacaaggagttgcaaaaacagtacagagatttcctg tgtatacataacccaactttccccagttacatattaaccaaatacagtatattaccaaacccaataaa ctgacattggcacagtgcaatcaactagactgtagaccttacttggatttcacctgtttttgcacatg ctcttttactgtgagtcattatctgttattctatgacattaaccatgtctatagatttatatagttac taccactatcaagataaagaagtgtttcatcaccacaaagtaacttaaaggattatttttataaagta atgacaaatgtgtcaaaagccattcctgtgttatatagcaagtatgttttgagttattaaaactcact gatcatgtctttcagtgtcataactttgggtttccctccctaactataataatcctgatgaattacag ttgatgaatatgagaatatccaactcttcctgactctataaatatattgactgagattgtaatattta tggtgtcttaaggggcgcttgttttattatgatgatgtgaacatgttgagaatagtaagaacagccca gtttagcaaacaggatatgagtcttctatatccagctcaatcgttgccccaacaggggacatctgcct ttgctacttaattttccattctggaaaatgtgaagtgtatgagaatgaataatcgtctccgattttcc agcacataataatctgaggagagcaggtacagcaatttaggagctgttttcttttggtttccaaaaaa agttccgtccagtggtctaagttagtcgtttactaagtgatagagcaattggctatgctttttgaacg gactgataattatgtggatgcagcaaataggatatagacaatgcatctactccattacagtaaaaaag actctgatagcagttaatccacataccaggcacttagcttaggcacagttggaggaaatggaatggta atagactgtagtatggcatgacaggagctgtagcttgagattcagaattccaactctgcctctcaata tttgagtcctcatggccaagatatgtaaagtgctctgtgcaggtcttggcaaccatccaccacacact tagtatgcaatatctatctttattagtcaaggatctggaaagctagttgatgagacaaatgatagaaa caagagttcattagatgaaataaagtaataaatgatgcaagaatttaaaaaagatttagagaaggaaa gggaacagaactcacatgcaagtagagcaactgtgtatcagataatgtgctagctgagttagaaacca tgtctcatattaccctgaaaataattctgcaaagctgtaggtgttatttttttcatttgacaggtgaa ttcatgaaggcttgaatatagggttaagtgagttgtttcaatgtagttattgattcaaatcaagatct gaatgactctaaatatggtgctatagagatttgaagtaggataaataggatttgaaaaaaagaaaaaa tatatagggaaaggaattggtacactgtagcagtgtcataaatgaagcttcagttgtgtgattccaga tgatgtatgtgaggcctaatcaaacagctttgtggaatcaaaatttctgctcttgtctccaactgggg acgagttggctcgggattaaggtgggcgaccttgggaagactagagtctaagcaggactttagtccct cataagaattatatgaggatgtatatttgcatacaaattcctgggcccaccgagatctgccaaattgg aatgtgtggtgatatcacccagggaaacatagagagctgttataattagtcatgaaatatttagtact gaaattatagattatgttaaataatcacttataggggacatagcagggttggcaggttaaccatacag caaacagggttgtaagtcagggcctagagaattttcaagaggcaggaattctgcagaatgaaggcctg gtctcatgcagcaccatggacagctccgaggcactcttgtttctccaaaaacctgaaatcaaaaactt tgcttttcatcatgcaacatacccatgtaacaatcctgcataggtactccctagtccaaaattaaagt tgaaaaaaaaaactatactttcatttgaatacagttctcttcggctttaccagctctactctggaagg aatatcttttactcaatgaaaggccatcccctgttaatgcctggccaggttctccttatcagtcattc actatctttgtgtgtgagtgactaaacatataatgctatgtttagtggatggagtaagattacctttg cagaggttgtactggcttacccctttggttcttgtagttttcttctattagagttttttccatcccta ggtttctatactgttcaaatgggtttaagattcttgaaggtattcctctgaccttgtaatttatgctt gtctcctagcacaacttttttttgtaaaggaggcaccaactatgtggtttgctggcgatggcatacac aaatcaggtgggaggaattaatgagagcagcaattccaatatctggttcttcaagattaacttgtata gtttaattcagcattctaaataagcctcatagatttaaaaatctagaataaacccacatttttaaaaa aagttttatgttatctgtgctgataatgcacgctgtacataataaaatattattttcttttttttaaa tttattattatactttaagttttagggcacatgtgcacaatgtgcaggttagttacatatgtatacat gtgccatgctggtgcgctgcacccactaactcgtcatctagcttaaggtaaatctcccaatgctatcc ctcccccttccccccaccccacagcagtccccagagtgtgatattccccttcctgtgtccatgtgttc tcattgttcaattcccaatattattttctaagtggcagtggaagaaacatggaaagttctacttcatc catcggtggattagaatttgtataccatgagatgattaattttcaaaaccagtttgaatctcacaaaa taatgaccctgttttttgaaggacaaggcagaacaaggaactaggctgtgccacgttcaagtcacaat ctctaacatttgttttgttttgttttgttttgttttgttttgttttgttttgtttaatctctgttgct tgttcactttctcttgtaatctgcattgatttgctacctggctatttgtagattgacttcggctgcca ggaatggaatgtttttcataaaggaacatatgccttaatgaaagtaccataagaagggagtagagtgt gaccaattgcctaggtaataagtagtgacaacaatgatattattctagtataaatggaatcagttttt ctttgcccagggggcatgataaagaaggcctggctggtatatactaggtgggacacaccaacagtgcc tagaatgtcaatggatcaaacctgagggaaccagaagttgaaaagacatatcccaaaagaaagcattt gatgtttaagggttggcttacttagaacacaatgaaaaatattactaaaattaaaactatgattttag ctatttttaaatatgacaaattaaatagcagaacattttaataaaacattacttaaggtccacaattt tctgtaagtctaatacatgggtcattaaaataaaaaattccccatgatttatggaatcagattttttt aatacaacgaattctaaatggttttataatgccaattccaattaatatcctaattataacatgtcatc cagaagggttaatgactaaattttattaatatttgttttctatttattttgatttgtgcagtttatgt gtatagtaacgatagctgcaaattagataccattagcattaaataaggtatatattttaatagaaaat taaagttaagtatttgagctagcctaaaatattcaacaacttaaatttgttttttgtggatcacattt ttttgagacaaagtcttgctctgctgcccaggcttgagtgcagtggtgcattcatggctcactgcctc aaccatccaggctcaggtgatcctcccacctcagcctcccgggtagctgaggctactggcgcacgcca ccatgcccagctaattttttgtatttttttttagagatggtgtttcaccatctggtctcaaactcctg agctcaagcaatctgcccaccttggcctcccaaaatgccgagattacaggcgtgatccagtgcactca cccctgtgaaccaccattaaatagctaataaaagatgcatgtcaataaaaataaacaacttactagaa tgattatgtgaaaatcatttattcttccaaagcatgaattttcaaacacaccttttgttactgtttta agaagggaatcatttccatatatttgcatgtaaatcacttttagtctcagagaactttccataaaagt ttttttattactgctgtaaccgatagagctagtggactattaatttaaaaagctgtacataaaaacac atctatagctcaaataatctaggataccttttagtttggggaaatgtagatgaaaatgaagtaattac agaatccttgttaattttcagatttagacagtctaggcaatatctttcaggaatgaagagatatgtgt tttttggcatcttggtagagtatattcccattgtaattcttttgtgaagtctagaccagatgtggcca taaaaatagacccctactacaataatatatttcatagataatccaataaagtcaaatcttattgcagt aggcttagaactctgtttgcacccatggaatttatatcagtttttggcaaatcctttcatctctgagg atactttttcatctcacatataccctattttctgaacattttgccttcaaagtatacctcatttatca agaatttctctttattcatctgacttatacaagtggcaataacaacgtctggttcccatgaagtaacc agtgaccctttgaaataatatagcgctggaagaaagaaaaggaaagggagactgatcattcagcaact ctttaaaaccatgtcaccgttaaacacatagtttattttatcttttttttagaattgtgaaaacctat attagcatcttcacggatgtctcctttgtttacatccccgcttctgtgccttgcctgcagtagaaaaa aaaaggacatgtgtatccctattccccattgtcttctcattctacatgagaatgagaattcttttaat ttcttctctatctacatgaacccacttccattatctgtttgttcagttctttaaatgccctgaagcta gctctgtgactgggcagttgaaagttctggacttagcatcaggttaatttgaaaaatacttattgagc caccaccatatgtcagccactactgtagatgttttgaatgtgtcagtgaacaaagcagaaaagatgta tgccctctggattcttgggggtctcaaatagtgaaagacagatacgataagtatattgtatagtatgt tcaaaagtgataagtgctgtgaaaaaaaagaagaagggtaaaataagagatggctcatgctggagtac attccaattttaaatagggtatcatggtattcttcattgagaaggtgacatttgagcaaagatctcaa agaatgaggcatggggttgaatcatgtagatatcagcagtaaactcattttgggttcagtaaacagtc aatgcagaattcctaagccatcggtttatctgctgtttggggctggttatctgcagtgtggctagagt gaagtaagtgagagaggtttaggagagaatgttagtgaggtgagggtggacctttgaagccattgtaa ggacgtttttctctttctaagtgtgagaagatgatgctgactgagaccagggtgataagaaatagtca tattctgaacgtgtttggaagtggggccaacaaggatttctggatgaattggataaggggcatgggag aaaaatggagtcatgaatggctccaacgtttttgctctgattaactggaagggataaagttgccctaa actgaaataataaagactatagatagaatggggcgattagggaggcattaaatttggatatctgttag acatatcaccagatatattgaataggcaattgaataaatacctttagagttcagcaaaaaaggtccag gttggacgtttaaatttcggaggtgtttgtataagataacatttaaagctgtgatatcagattgtatc actaaggaagaatatagatagaaatgacaacgtgactaaggactctaacattaagaggtggattgaca aaggagaaaacagcacaggataatgaaaaggaatgatcagccaggcatggtggctcacacctgtaatc ctagtactttgggaggccgaggcgggcagatcacgaggtcaggagttggagaccagcctggccaacat ggtgaaaccccatctctactaaaaatacaaaattagctgggtgtggtggcacacacctgtagtcccag ctgctctggaggctgaggcagaagaattgcttgtacctaggagacagaggttgcagtgagccaaaaga ttgtgccactgcgctccaacctgggcgatggagcgagacttcatctaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaagaaaagaaaaggagtgatcaatgagatgggaagaaaaacaaaagtgtgtggtgtcctc aaaaactgacgttctattttcaaaacctacattttgggtctccttttactatatcctgactttctagc tatataaccaaaaggagaaagcagtaatttttttagatataacatgttaataactctaagggtattca atgaatctgaataattcagtggtataatgtgaaaaaatatagtattcataggaaaaggaacagaagtt agctcaggaaatgacttgaatgaacaccgaagccaaatctccagcgcaggtccacgtattatttgtct cagtggttgaattagcagcaagattccttagtaggatgaaaaaagatgttgtgagcatctgtatctac atgactgaattaaattcctccaacaatgaaatgtagttaacgtagtatctcgaaaagaaccctaagtg gaattcagggaacctaaattccaaccatggttttgctgctgactgattgcattcacttcaaatctatc attaacctccttgtgcctcattatcctcatttcaccaaataagaaaaatgaaatattcctccttccct acctcactaggatgttgtggatttaaatgtgtgagaagtgcttgagatgcataaaatttgatggagtg ttttattcatgaattcaaggcatctgaagtaatttgaccatgatggacagttgcttccttgcacattt tttagagtgacatttccgttactgacccacccatttatgcaacatgttgcctaatctaaatttaggtc aaaacaaattgaccttataggtaagcattatatctattaatattgtatttttgtattattttataata ttcatcattcacctattttctcatgcaatatatgttactgaacacatatagattaaaaagccttcatc cctaaataacaatgatgggaccttccatttttatatccctctggcatttaaaatgtgcttttatagcc atcatctccattgatctctcagtcccttgaggttgatatgacagatatgctttttccattttaaaatt acggaactgacagtctcagatgactttaccctccaactactgtgtgaagaagcagggtctggcactga ggtcttctgacatccagtgtagagcactatacttcacaatatggccattggcttactttattacaagc actaaatattttccactgaatacgtaatacctagaggagaatgtcgtgtaaaacagcagcagtagaac agaggattaaatgacccattttcttgaagttatcttagttttaaagggttttttcttcatcactaatg accatccctgactaagaaattattctcataatacatgataatatctgcgttttccaatgcgacaagaa tgttaggatgtctatacatgatcttgacaatccctagctccatcacaatgtgtccaaattcattttat 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tggataaaactcgcaggacttcagttctcttcatctacacagtgagtggttagattggctttgtaatt taaaattaaacagggtttgattctgattcactacacaaggttccaaagaaggaatgatatctcctttc atttcttcactttgtcttctgtccctaggtaatcttatctatgttcctgatttaacctaactaatgtt tctgcaaagcttctaatatttacatctccagccctgaaactctcatttgaatgctagtcttatataca tacccccctgcctaattgacatctccacttaaatgtatcagaggcaactcagactcaacaaggaccaa actgaatgttcgaccttgtccttcaaacccgatacacatccaggttcctccatcccagtgaatgacac tatccagttaagcaagccaaaagtctggattttttttcctcactcttcctcactgtccgtcaactacc attattaaatctgtcacctggtcctactgatttaaccttctcaatatctctacagtttttctttatgc ccattagtatcctagtgcaagctaccatcgtctctcattggaattaacacagtaacccccctacccac cagactgttctgcctacagatagtgtgatatttaataaatataaatctagccttggctagatttctcc ttcaaaaggttcacattaattttagccttaaaatggtgtgcaaagctttgcatagtctgtcctttgct atgttggcagtattttttactatccctctcatctgctcattctctgtactccaactacactaactttg tttttttttttttttagatttctctaactacagtgctgtaatctctttttcctttgcacgtactattc cgtttgtcagggaatctgctcactgtctccacccactccacacactcacgttttcctgcccgtcttac cggtcttgatcggttgtcacttgctcaggaaggtttccctggtcaccccctccacaaattgaattaag tcctcttgctgcatgctgtcctagtgctctttattttcctctcctcatccttaattcagtttgtaatt acatgttatttgtgtgaggatttgattattatctgtgtcacccactagatattgggcattctttactt actcaccactgaattcatagaaccacagtaattgtacacaacaaatattcaagagaaatttattgaat tgatgaatgaaaagttgtaccttaacatgttcctgacatgtatccaaaaaagagctcccctttggggt ctattaggactttggacctaggtaaacgtaaccctagtttcgctcaggtttaaacagtagaaagtaat tgggtctcttttgcatgtggctttcctaagggctaaccctgtcttcggaatgagtcaatacagcagag ctgttgaaagcagactctagcttcggacaacgttggtccgaatcatggttccgtcatttcttagctgt gtgatttagaataaattaatgttttaaagctttgatttcctcttccttaatctggagatgctaataaa gccaacttcgtagaggtattgcgatgagtaaataagcataatttgctgtaaacaccttgcagattgcc tgttgtatgctaactaatcaataaattgaagctcttaacatcattatattagatatttccagcattga gtatactatcaggcatgtggtagaagctcaatataaagttttgttaaattgaatagattccatatatg gtatttctacagcattatgctccttatttaagtgtctctaagtattttttaagtatcacctcacaaaa gacagatgtttaattcattacacatgtgaattgttttagatagaaaataaaataaaaaattcaaacat 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tccctagttcaccattaaatcaacttattttctcttaccccctcatattcacgtttactccttacttt gtagtggttggacaaaaatcaaataaatctgagaattctaaaatgcacacccttgtttattttctaac tcaaatatgccactgttgtctgtgctctgtcaagatttcaacacatctttttctcctgtttgcttttc cttttggcatatagtgagtgtgtgtatacacacacacacacacacattttttttgactccttccaatg cccttctgctctccgcagatacacttctgcattctgaataaaaccgaatacatatatatatatatata tatatatatatatatatatatatatatgcacacatattttgaaaaccttatttgaaaagaaagctttc ggaggaaacgttatttagccacttaatcgagtcttttactgagggactttttgtcgtcccctaacttc ctgtcagcagtccacaggcagcaggaataatgtgggagaagatcaacaggcttatttcaggaggtcag gggccagtgccaccacctgcaggtggagacatcagaagcaggaagcagcccaccagctgcagggagaa ctccccacagagcctaaccaagatgaagggacttgtaaatttcaaccctcccttttggcttttgtgct aaaaatgtgaatattgaggtctgccctgattaagaactagatacattcctctttgtgactgccacact tccttagcgtattcattttttgtctttcgatctcaagttattattttcaaatgcattgcacgtatcta ccatggataccattgcaattggaaggagcaaacgttttgtatgtttacttgacaaagagaagtgactg cccaagccacacagagttctgcacaaatcagtaacttctaacgaacgtttgcacttccgggcttgttc tctacctatttcagtcgatgcatttgtattatttacttcaaactccaatactaataatgcctcaatca ggttgcaattgggatttgagcagccagaatttcagaaatttggtttggtccatatctgtgacaggtca gtaaatcagagaagcaagggtttggttgctattataatacattgcttacctatcaatttagttatcag ccaaggtggttgttatcatccaaagtggctcattaaccaccttggagactcagtatacaattgcaagt aaccctggaagttgtaaataatcccaactgaatttgtatgagtttggtaaggttaagtggaaaccagc tgcttagggccttgattataaatgaagttaggagtggaagaagtaacaaaaccccaggcaaattcatt aaacattttttcccttcaactttatgctcacgaatgtgttgagactcttctgaatccataaaacacct ttcagcatcatctgggcagcttgataaaggctgtagactgcctgcccttcatcccaaacctactgaat cagtgtctgtgtgtgaagacctagattctgactggtagttataccaaagtcttagaagcaactctagg ccagtagtactcacgtcagaatcagctggagggtttgctataccacagattgctaggctagccttcaa agttgctggtccagtaactttggtgcaggtccagaatttgcatttctagcaagttaccaggtgatgct gatgctgctggccttgatcatgctgtgaaaaccactgctttagctaggctataagaaaccatataaca tggacaaggcaaatgaaaaggttggaattcttctgaatcccaacacatttgtgagcataaagtcgaag ggaaaatgattcttctgaatccagacacatttgtttaaggataaactgttttttccttctgaaaattt 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tctcaaacgcctgacctcaagtgatctgcccgctttcctttggcttttaacactatagagcaagggtc cccagccctggggccacagaccagtacaggtcagtgacctgttaggaaccggggccccacatcaggag gtgagctgcagggccgccagcattaccacttgagctccaccttctatcagctcagcagcggtattaga ttctcataggatcacgaaccctattgtgaactgtccacacgagggatctaggttgtgtgctccttatg agaatctaatgcctgaagatctgaggtgcaacagttttatccccaaaccatcgcctcccacgcacctc tccccacaaccccacccgcccctgatccatggaaaaattgtcttcctctaaaccagtctctggtgccg aaaaggttggggattgctgctatagggcgatggttttcacatttgatcctgcatcaaaatttccaggt gactcattaaaatactgattgctgtgccccactcgtaggagttctgataaggtagctgtggggtgaga cctgagaatttacttttctaataagttcccaggtcatgctgatattgctttgataaccaaagcaatat cagctttggttatcaatatataaccaaagccacatagagggggagaagttccttgggtttagcccagt gtttactgcgaccaccaaaattgctggagcttaaccatggctcagagagttatgttctgttcactctg taggctgctattccctgtcaccttttgaactatgatggaggggaagagctgccagctcaggagatttc acttttttctctgcataattgaaaatccagaaacacagggttttgggaaagctatagaacagatcatc agtgatcagtgtttaataaagtaaagcaataaactttactgtgtaaaataggatactttattatataa attttgtccccttcccccacctcacaggccaataaaataatatacttcttgtccctgggtgtaatgtt attggaaacctttgaatgtaggagaggcatgggcttgtaagttgcagaaaactgctagcctaggattg agaatttcatggataatccaaaaatagatgattttacagttataagccttacgtgaacttgaggtaag aaaacacaatgcctttatagtcttctcagttgctccacatgccctctgagattctgttctgcccagcc tctctggttgtcacatctctgggcattaacagaaagttcacatactctttgtctctgatgataatcct tctaggtccatatagaagatccctatccaaaccatcccccaaacaaacctattggttaaatattttct ccaccgaaggcactttcttagattctaagtgccctgtaggcaggcttcctctctgatttgggagagta caaattgcgacaaggttaaatcatagcctgggaatttgacctaaaattcactcttctcccatatgcat tcatgaaccttctgctggtttttaaaagaagctacttaatgtcagctcgaagaggttggaaggggtta aaaacatgagcatggcagtaagaagatttatgaaggatctgagaagattatgacttgatcagatggta ttttgtcagctagccacatttgtgaagacttgaaaactagggaggcttgtccttctaagagggggcac tgctgggacctggattctgtggaaccgtattagtagaataaacaataacctttgcttgtatcaaatga acttctattctcatgtgtcttttgacatatttttattaatcatatcactgggacctccttgctgaaag atatctccgttccccattctgatgactcccaactaggagtgagatcaaatgaagatggcatggaccat ttctccatgtgacagctctctgtggttgccttttaacacttctaatgccctttctcttaagaattccc atttgtcgtctggcactggtgctgtgatcaataaaaatgtaatggagtgaggcttagaaacatgagga aatttactcaagctatccatttattgatgtgtccatttgtgttgtcagggaagaaaaactttttcact cccctcttaggttcattacttggggggctgcaaattaaactgacgacagatagattggcaatagaaaa gacaaagtttattcagagaagtatgtgggagctcacagaaaacatagctcaatgaagttagaatttgg ggcttatgtactattttaacaagggttttgaaaagaagagtgttagaatttcaagccacaaagttggt gggaaatatgaaagaaactaatgaaaggtaatgtttgttttagtaaagtctgtttatgtaattttctt ttcccagcgacaacttctcatctctggtgacaggagtcactctttacccctggtgcaagaaactttcc ttaaaggaggatttaaaacagttgaattatttcagaaatctttgcttttaggcagatagggggagtac agaaaaagccccttcccgtatctgttgatcctcaaatggctttagctcaaaacaatttttacatcacg atggcataatgtagatctcttcaatgtgttcatttattccacagatatttgtgaagtacatgatatat gccaggtacttgggatacaagaatacataagtatgtccctagtctcgtagaacttacactctagtagt gagctagagaataaatgatattatttattatatgcatacacatatgatttcagatagtgatccatatt ggaaataaagctggttaagggaatagaaaatgatattgaaggtggacttgtttagattgggtggattg gcatggcttctctagggggcagtatttgagcagatatgagagcagatattctccaatttgggcaaaaa cattccaggcagaggaaacaagggcaagggcactgagttcaaaagagacttgacctagccaacaaata gcaaggattccagtgtaagagaaggtggggaaggaaggaggtgcaagtataggcaagggcaagatcac acgggatcttgcaggccgtgataaaagaatttaactctttcataattttgacaggacatcattgaaga atttagaaaaatagagtggagatacctgatctgctttcttcaaagagttcattcatcattgctgagta gaggttagactgaaatggaagcaatagtgaatacagggagatagcacaggaagccacgttactagtcc acatcagaggtggttcagactagggtggagtggtggggtcagttagagagctggtatttaggatacat tttaaagacaaagctgacaggatttgctgtgatgaattagatgtaaagtatgagaataattgagaatt atttctaagttctttgctggggaaaagtggaggaggaaaaagttagggtacaaggtgtgatgaaatca agagtctctcttattatcagagtctcattagatatccaagtggaaatgctggaaagaaagttgggtag atcagtctgaagctgaagacagatactgtgactggaataataacgtaagagttggccggacacagtgg ctcactcctataatcccagcactttgggaggccaggataggagaattacttgagcccaggagtccaag accagcctgggtaacacagcgagacctcgcctctacacacacacacgcgcgcaaaaattaatcgggtg tggtggcacatgcctgtagtcccagatactcaggaggccgaggctgaaggatcacttgagcctgggaa gtcaaggctgcagtgagccgtgatcacaccgctgcactccagcctgggcaacagagtgagaccctgtc tcaaaataaataaataaataatgtggcagtcataggcccttagatggtttttaaagacatgggactgg atgaagtcttctaggaggagagtttgggaaaagagcccgagaattgactgcacctttcaaaacaggag gaagaaaaaaaatactcaaaggagacaaaagcaacttctgtgatttatagagaaaaccaggcaagtgg gatgaagaaagtccttcatgatagaatcaaaaacagtgtcaaatgttgaaaatacaattagacaaaca caaaagaatagaccattgggttttgcaatatggagctcatacttgaccttgataaaagacattttcac tggaagcatgcatcaaaaaactatttgtggtaggttaaaatgtagtaggaggtgaggatatacagaca gtggctttcactgtgcagatactgctgctcatgcactaattaaaagacatttgttgagtatctactat gttgtatccattgctaaatagtaacagctgggtttagtcaggtagaacagcatcaaaatcattatagt atcccaagataggtacagtaaaatctgtgaaggaatcagagtagtctcttctccaacagagcgtaaga cccagcttcacggagaaggtggtagattagctcatctgggaggctgagtagaagcttgtcattataga gggagaacatcagaagtgtggacaacagcttgaataaccttgaaaggacaaaagaggacggtctgccc tggaaatattaagaagtctcacatgattagacacaagatattaggggaaaggcataaggtgaattgag tcaatgaggtcaaagagaagctagctggaggaacaggcgatcataaaatgagtaaaagtatatattca aagattctttttagaagggctacacaggatggataaggggagagagagagttgaggcacagagacaaa ttggaaaggtgcaatcataaccagagacatgaaaaacccatagaaatctgatgtagattatgtggtcc ccaaggttgaacaattaagtacgctttcagttgttatgcccatgatattaacatattttataactgca ataagtgctgaagctaaagataaatacaaacaatgtaattcttattctgtgagaaaatgttgtagctg gaagttaaacatgtttcttagctaaagaaaaatattgtgtgatctggattacttaatgttataattta gcaacaaaatgttgacattgagccttgcataatcaaaaaagtagtctattcaataaccacattctcag aaaaaaaacaagaaaatattagaaacaatgataaattatcgtagtaatttaattcagtattctattgt tttatttggatttaggaaaggcagaaatgttgaaatattaatatatatccctgtaataatataatttg tgtctgagaggtaggaatgagggcatgaggtcaaagtttgataatgaacttcaaagctataactatga tcaggaaattaaaattggacaataaattcctagaatcgtcaggagttgcttgtgaaatcgagaaagga aaggatatacacaaaaataaagaacagccaatgctctcaaaggagtctaacttttataatagtcttct gtgttagagctgaactcttctggtttagaaggacactctgttgcctggaaatagggcatggaaaaagt catcagagtcatgtcatctttcattcttcccatgaacgaaatcgaggccctgaaaagtcacctgtgtt tgctgtattttattgcaactaagatgtgcatttttaaattgatacataataattgtacatatttgtgg gatacatgtgatattttgatgcatgcataccatgtgtaattatcaaataaggatatttctgtatccgt cacctcaaacatttaccattgctttgtgttgggaacatttcacgtattttattatagctattttgaaa tacaaaatagattgtcattaactatagtcaccctactggatgcaccttgtttttaatatttctgaaaa cagatacgtctcataggtgatggtgtcacagctgtgcattagttattattgcctgtgcaggtgcaaac gtaactattcatattgttgtcaattaattaaatagttacatttatttatatgcgtttattatactaat aaacacaatattgagatagttgagctctagttttgactctgctgttaactagctgcgttactttaatt tacttaactaatttggctttcaaattcctgataagtaaaattacaacatgagtttctcctgctataat agcctgagaaatcggtgaaacacatgaattcagatgttgatgctatttaatagcgggattccagatat ctacttgccattatgggagggagagaggaggtggactggaggctgtgatttccctaggaggttgttaa aattggccaggtgaggaaagctgagacagaccataaatatgaagcatgatacctagccctcagtgttg aaagaaaatcaaatctcatctttgtggtctaaatatcagtatgatacaatcctctgtgtagacatatc ctctgccctattgttttctttctaaaagctaaagcccaggtgtgatcacatccctccgttatttacaa atttctgatgatgatgattcttctaatatctacattccttaccattaccatgatgtccaaaacctatt ataatctattcgtctccaagtgccatgttgtggtcaccctatgcaccctctaaacccaccatatgacc ttcccgctgctacttgaatacagttggccctctacctcgttgtgtctttgcattgcctatttaattgc ctttccattctctaaatcactctttcgctggaccagcaacatcagcaccatctgggaattcattagaa atatagatcctcaggcctcatctcagacctgcttgatcagaaacattggagagtggagatgagcagcc tgtatttttatcagccctctaggtaatttgatgcacactaaagtttgagaaccactggtctagagcat tcttctttaactctcttctaaaaattattagaatgaattcgagggacgggatctccttgaaagccaag aacatttctttgtcatctttctgacttcagggcgtagtacactttttggcccataattaaagctcgat aaatgcattctatgccaataaatcagctaatcaaatatattattcatgcccttgaggtatctgaaatt tctttgcagaatgtaatatataactatagagtaacaagagaataatttattgccatagataataaaac aatatcctctgtataataaatcctagcctctgctcaatgggcaaaaacgggactggggtttcagattt taaaaagattattggtaattaaatcacctggagaagcacttgctgcagagatgggacttgaagcatca taataaactgttgtttattatgattcggtcagagctgatggaatcacagggattgtgtgaggtatgga aagtggttgacattgaattccaggctgcacagttgggacttgatatgataaccaaaaagaaagaatgt ctggggtggtagcaagctctaaatttagacaatctaggcttatcctaaggagaatatagatacagata actgaagtttgattaaagggaacctggtgtatcacaaatagtaaaaagctgtagttagtctatgcagc tatcagctagccacataatacttttgggcaaatacattataaaccaaaagaatgacatggcttatctc tgtaacaaagtggctcattgttctttattctactgttatccttaagaaaaaaattttagtaaatttgt tatgctatactcaacttcaagaagggatagcgcttataaaaaaattgtttaaagaaacaggcctattt ctctttgggagaagccacggagaaacgaaaagaatggaacgtgtgtttctgcccagatggcaataaaa tgtagggtaaatttctgtcttttaaaactgtattttttccatccctctgtatatacacatatcctagg actgttataaaatgctgcatgcgtatgtgaaaatggaaccttattgggctgtttgatggacctttaaa atatatttgttggtttggggtacatactagctatgcaatataatccgcattatttcttatgtaaacaa tggataaactgtttcacagtccagacatttatttggtcactgtttgtagaatgtctattttatttact tctgaatttgtattccagagatctgccttcaatgttggatacttccactgtaatattctaggagatgc tcactttctttttcagcatctgacacagtaccatctgcctcctcttttcttgccacaagtaataacaa ttttataaaggaggatcacattacagaattataggtggtaaactttctaccaccagatttacccaaga acctgaaacacattttttcaaaaggaaatagaatgtccttcttgtgactacatcggaattttgcttgc agcattatgctttttttttccccctagtgtagctagccatgtggaactgaagccattagccagctcct catcctataaatgctattacctgggaaaagaggcagaaaatatactctcttctccagttagagtctaa aggaagagaacaatatgggtagttgtgtttaccacaaattgatagaactcctttattttaaatgctaa aaccaaataacttgtttatatgacttcaacattgactatcacacactgttgcatgataacagagtgaa aactacctctattggatttaagtggggaatctatgtctcattctcattctttttttactgtggaaact agttgattccaggatcagccttagctccaacttgccacactttgagttttggtttttcacttgcattg tcacaggaaacttctataggataaatcgaggaagattttactctgcaacgtgttgcagaattaaacat ttaaagtggcaaaaccttcgtgtgtaggttgtctccccagagaatgtaaaaatgaattgaaggcagca cctaataggtaaacgacagccaatcaaacaagaacaaatgaaatttgactggcaaaatcaaattgaaa atgtataacgctgaatctcagaatataggaggatgcatagaaactaagctgtactattataaaagtca tagccattgaaaaataatgactggttaatttggttttctttacctcatggatgtgaatggttagattt tgatgttggtgttatttgacgtgtgtttgtcaagaagttgccttagtcggctcgcatttaggataaaa aaaatattttaagaaatgtttaagagattatgttggagacattagaaacaaaataattatgcagaggg caggactatcaaaatataatagaaaaattacaccgctcttttatgatttcctcctttttggcatttaa cacaaaactttatgattacacacaccacgcactccagaaatgcttaaaggaagatgagaggaaaattc aatagaagtagcaggcatttctgtgaggacagcagaatgatcacttcatctctgtatttttttttttt caaatttctgtatctgtacaatgtcttttccagctctaatattctgtgatttggtaatttccgcactc agattttctttaatgaattttgtatgatattacctatttttataccagatattacctggctctaattt ctttttcaccctaggaaataaaagtatcgggtgaatttcccattttcttatgttattgatacaggtct ctgttggatatccccacgattaactttcctgcagcatgttcgatggtggcttaaagaagaaaccatgt atcagagccccttgtctatatagacttttagataaagagaaatacatatcacagaattattctgggcg catagagtctctaaatgcaaaaaaaaaattgtattgtagctgttgattcttctcagatagattgagtg tagagagagagcattccaaaaactgagcagaagaaacacagtctgaatcaaataacatgaaattttag ctaacaagtaaataacacttttttcagaatatgcaaataatattggtttattatgaaaaatgtatagg ctgatagatgagcatagagaaaaaattataaatatcttctttaatatcactttccccagcaaaccact tttaacattttgatacattttcatgttcaaacatttcctaatagtcttttttcctgttatataaatat gaattttaaacattcgtatgtttatgaaaaggcaataagatactgctcttttataacaggctttctga acttcacaacatgcagtgtattctaacatgctccttgtgttcttaactaataaaaaacctcacgttat ttaaaaaaccatcttaaacataattatccattaagagaagaggttggggtagagagtttcagactatc aatatcaaagttatattttctgtaagtattttaatttttaagtgtagctataggtatatgattataaa accaatagcagagaaaagataccacctttgaatatagttttccttggttccatgaaaatggcctcctt tctttttgccagtccctcagtatcattaactcatttttctgtaaatgccatcattgtatcacatgtcc tcaggaaaaggcacttttctcttttaagctagtgtttgttcttgttctaattttatggcaatttaacg agtaacaatcctgtttctataaatactgtttcctaattaatctattgcattctatccatgagaattta gatgactttctttgtaagagaaatctctgtagcatgagattcttctttgctcttaaatttcattcttt cacatttttaaatgacctgatagtattttgttgtatttgtgctgattttttttaaccaatcttacctt gttgaacatgtaagttgtttctaatatttgcaatgatcaaaatgtggatccaacttcactaaagcgtt aagaatctaaaacaaaacaaagaacaaaaagttggctgtcatcttgcttggaccaccccgtgagttac tattttcttgtttccggtcacagttcatcctaaatcatttcagtacacaaaatgttttttaaagtttg ggacagggggtagagaatgtcaattattcctccaaggcagtcatatgagcattgagtatcatgtggaa tagttgttacttgtaaagttatggggcatcaaacccagtcaatatgtttctggaattgaaaaagtccc tggacattctaatgatactgttgttcactttgcacctactgttaccactactttgatctgtcaacact gcccgtaatggttaattttgtgcatcaacttgactgggctacaaggtgcccagatatttggtcaaaca ttattctgggtgattctgtgcaagtgttatcagatgagattaacatttaaattggtagactgagtaaa gtagattgcccttcctaatgtgagcagacttcatgtaattaattaaaggcctgaatagaagaaaaaca ctgaccctcccctgagcaaaagggaatcgttctgcccgactgccttcaaactgggacatgggcttttt cctgccttcagactttaaccacaatattagctgttcttgtatctcaagtctgctctacttcgattgga actacactatcagctctctcgggtctccagcttgcttgttcaccctgtataccttgggagttgtcagt ctccatagttgcctccataattgcatgagccaatttcttaccacatacaaacacacacagagacacac acacacacacacacacacacacacacacatataattatatatgtgtgtgtatacatattctcttattc cttttgtttctctaaggaaccctaatatactccttattactctttctactgccttagagatcttcaag gccaagagcgtaatcctccatcctggctctttttcctaatcattaatgatcaactcatagccatttag ctcaactaaaaataatttgttcatgaagctttacactcccacatactgaggaacgtggtacctaagat caaacagtcactgcctcatcaaatgcattcctcttcaaccccatacaaatgtccccagatggaactca caccataaaaatattagatcccattgacttttctgctttctcaaggatcattgcagagcttgaaaaag atggctcctccctttgcctaagcaggttaacttggtgtaaaagtacatgtaagatttggcacaaagga aaataaatcagttttgcctgggtcctaagaaacatttccctctgcctcatggtaattgtacctgccag ttgattgcattactcaagtggagaccatgaagtgaagtggtagaacaagaagaaatccctataatttt attaagtatggtgaaaaatacagatatgtagagaaatgactgggattagatggagcaaaacataattc gagatcctgatacaaattgtacttcctggctcaagggagggagcagaacattccctgctacatgggaa taataataaatgcctgataaaaatgcagatatatcatagactacagaagctgaagtggattcttatgg tcccctactcagacagcctctccttcagatgaagaaactgaagcacagaaagctcatcctagtgtttc atattgaaaaacccattcaagtctattttaataacctgttaccaaaaatgagggaaataatttaactt taatgtttcactttgcattacccttttcctgactagacttctatccttttcttgagttgagctcatta actactatgaaattatggttatgggtagaggttaattttatacctgtccatcttctggcatcttattt acactaaaaatcatttttaaatggcttcattttaaaaaatattatttcagttgacattttaaaagaca catcatttatgtactacagaatatgcattttatactctcctttattaattttattattttccaggtag accaatcaaatgaatcagaaattcttggttagatctattagacagcataagtatgtttttcatcatta aattaagatgaaaacacaattttactttaaagtgtttgacgtttccagcctttataaagtcaacactt aatcacatctgaaatttgcaggaaaaaattttgaaagccttcaattattaacattatttcgggagaaa aagccactttgccgcagaactttcacttttctctcgtgaattaagtctgatacaaattattcattatg gtgaagtttaaacataatagagtctagctacttccacaaaaatactattcaatgagtttctacattga catctaactgaccttgtaattaatgttgtacacgatccttttattatatgctggattatcaaatatga cttattagcagtataaagacacaaagttctgaaatgtaatttatagccatgaaaaggaactgagcttt gtgtgacagttaaatttgaagagatcaggtgattattatgaagcatgaataataatgcatattaaact cacgtttttgtttaaatcattaatatgattgttttagaagaaagtctacctctatcatatgggcaata aaatgtgtataagagcaaacatttgtgtatgtgaaataactcaaattaaaaccagttttccacattaa ttcttacagtttttaaaatttaaatcatttaatgtatcacacatagctttattcattttaagctataa atgttacaatttctgtttaagctgttaatataagctttgtaagagcaattctgtataaatatagaatt gtcattattcactaatagctaccatttatttagtgcttgttgagtgcaaaagtactgcactgagatct ttgcatatgttctcttaatgttacaattcttacctgaggcatttctgtttctgctggaatatggtctc tctgaattgaacaagggaggcatttttggttgttatgatgaaaggtggacactgctggcactaacgtg tgttggtaagcgactagactcttcatgatgcgtaaacagtgtttcctcatacccctgcacattcaaat agaggaaaaccttgtttatagttaatttcccctagaatgtaaatccatttaacatataaacacaaagc gtgttttgtgtggatgttttttactggagcagggagacaggagaggaaatgcagttttgatagttgct gaatttttcaagaatgcagcaattatagaacaatttctagaagtttcctaggagctcttttccatagc agaaaactaggacttaatagccttgcgactcatggtacttgagtgttccatacaactcacctatattc aggggacatttgaaaaattctacattaaaggggattcttaacataggcgcaagtgtctggcatcttca ataggtcttctggtgtggccatgaaaacattcacacgtttcaaagtattttaaaataaaataaaacat atattgttgtgttatgaattattttctttcttttttatatgatggttagatcactgtgcagacaagtt tatgagatctattcatttcatttcagggtggtaaatgagggtgttactaaatgttggttctaaaaagg gagacattgggtattacagaattcagaacagctctaagccctgtgcacatttagcattagaggacaca ggcaaatctggcctccagtcctggcagcttcttcactatgtatatgatgttgggtgggttgctttacc tctctagtttttacttttatttctaagctagggctattcatagttctttatcatgtggttactgtgaa gtagcaaagcacctgacataattagagcagataaaatgctcaacaaatattgcttatcagaaggatta tgtattacctcccgaaatacatcaaaaatatattttccaattcaaagaatatgtagtacaaaaatcat gcctaaattaacagagttgcagtagcccaaggagagaagataatcattattgatttcttcttcctttt tgctaagcagttctctgtctctgcctcctcagttgttgtccatcccactcccccactcccaagccctg aactctgaggggtttgctgccgtggccggttctgtagtcattgctgtccaatgatgaaaacacaaaat actgcaacagaacactatgcctgtcagcttagctcccttctttctgctaaatgacactcaatcctatt cttttgttctaaaggatatcctaaatgaatagccactggggggaaaaaaggttatataagattgtgca ctgtgtgaaactgatgcaaccagatcaatgatgtgaatttctcttaactatttactgggatctagaaa caggtctctcaacttagcagtgtttacgaatataataggccttccttatacatacatctgaagccaat ctgagtcaggaagagtcgtggtctgataaatattttgaaaacttgcatttgttctattaaagcaaact gtttattaatagtgtgccttattttttaaagcaaaacatttataaacagtagtcattacaggcacttc agtgtacqgagtqatcaattgttagacctttaggaatcgattgtttcgtggagcttcggcttataatt gaaatgtcatcagaaggagtgtaagacatagcttcaggagaggccatttatgcgcttttgttttcagc taagttatagagtcatcatgtgaagaaagattcttctcttagtaaaaatcctttaatggttggaataa cacttgatatttaatatttctttctactttatatccacatttattcaagtgctaacgcgtgtggggca gcaatgaagcactttattccaacattatagttctcatatctgcgtatgattatttttcatttatcgtt agcatatatataatgatgacttttaaagtacactgtattatattcactggaataatgattagctatta ataatttgaacactatccaggaaattactgaacatgtcctacaagataaacctcgtatgatattgtct ccaaataacagtgctaaccaagaagagtgctaccaagttcaaaagtaatcacagggagtaacctaaat gcagctccgttgggttaaaaatagtttctctaaattatatgttccctaagtttgagatcgatttctac aaggggataaaatgtttttataaattctcagtgataagtcatgtgattaagaacccccaacttttttt ccaaagacatttgcatctctgatcaaaataacaagatccagtcttagttataaattggggaattttca tcaaaataaggagctactcgttgcataagaagactagtacaacttaaagccaatttaatttcaatgaa tgcatgatcagctccattgccaattgagtgtttttcttattcatcagaagatgggttcatcatcgtgt ttcatatcaactgttctcaaaccatattgcccatttaaataaatatagatttgtctcgaaattctaaa ttcatgtcatatttcataaatagcctatggtcctatttattactttaaaatattatagatataatatt tttattctaaagtaactgtgttatacaaccaaattattcatttaaatatgtgactttttaaataagta aatgacttatttaagtaaagtcattaaaattttccagtctgtccttcatccacctgatctttgaatga gttaggaacaatacaggaaactaatacaaacttaattttgattacaaaagatgaaatcattctgttat ttattcaacacactatgtgtcaataaaatcttatactgtgaaagaattcgtctaagtccatttgctgt tgcttgtaacagaatacctgaaaatgggtaatttacaaagaaaaggagtttacttcttacagttacgg aggctgagaagtccaaggttgaggggccacatctggtcagagccttctcccatccaagtactaaccag gtcgaacctcacttagcttccaagatcagataagagtgggcgcgtttaggctggtgtggctgtagact tgttagagcctttttgctcatggggacacagcagagccctgaggcagtgcaggacattacatggcaag aaggctgagtattctaatgtgttcatgtctctcttcctgttcttataaaatcatgaatcctactccca tgataacccattaacctattaatttatgaatggatgaatccattcataagggcagagccctcatgatg caatcacctcttaaaggcacaatctcccggtgctgccacgttggggattaagtttccaacacatgaaa tttgggggacacatttaaactatagcaaaattgtaataaaatgttatatagaagcaatgttcttactg attataattgttatattggtaaagtgttaagtcctctaaccaagggatatatttcagcttattataat agttttaaatttacaattcaatatgaataacatctggtaaaagttcttttcaagaaatgggaaaatta gaaatgtttagaagaaaataattcaataaatattaagttcaaactggattcatagtttatgtgaaatt ctgggaaccaattgcaaggggagaaaatagttacaatagcaatggtgaggatgagaataagagcaggt atcaacgttaattgagggtgtgttatagttctaatcgtgctatgcccactacatgacttttccctgtg tgaggtttccgagcttcttcgtagtaatcctaaattgagctggagagaggctagggtaacttactcac gctcatagagccatagagtagtaaaacctgtatttgaactctggcctgtctgacatcattctgtggtc ttttaaaccaccactgcttctccatattaaaactccaaatctaggtgaaaagaagaaaactcagaaca tgttctgcaacaaaatataacaaaatataatgtatataaacacttatacataatatcactaatatctt tactatgaaaagactctgatacgaacattttacataattcatgcagaagtgttaatcacattgtctgt gatgagctgtgtatgtatctgataaaattctggcaaccagacatcaactcgtaggcatagatctgtaa cactaaatatttgcctcgagaaacttaaagaaataaagacaaatgaatgaataggaacatggaactga gtacaagataaaatcctcctaaagcaatcgatgtacttgctgctgcgttattgttctaagcaaaagaa gcatggcgaagggagatgtgaagctaaaaacagaatgcttagaaggagatgatagcaggagggaagca aagatgggaccaagctcccaaaaggcgggctttgaacaaacaaaacagaaagctaagcctttgacgga tgcacgggatgcaagaaactttagtcaggaaagaggaggcgaagaaaaaccctccaaagaaaaggtga acaatattttaataggcaaattgacagatagcaagagatatataccatgctatgttttctcattgcag ctgaagacaaactggggttatttatgctttgaaaaagcgtaaatctaaaaaacaattgtggaggaaga agcgatgaaaacacgtgttaatacagaaaacatggctccaaggctttaaacttccttgtgagataaat gcatttacattttccgtagtagctaatatatatatatatacatatatatatatatatctgggaaaata atacacagtgattttctttctttttttcatctacttatgtgagaaaaaagtaggctatctgaaagctt ttcagttaaatgaggaagaaagttaggtgatcttgtaaataatatatatgttcaagataatgtaaggc ccttgtgtagttttcaaaacttatctttaatagcagtttcttctggggatggggtagttcaaagttga aatgttagaaagatgttaactttttttcctttttacttctccctttcaggatggaattaacaaatttg attacaaatagatctcagagagaggcaaatgcattgaatccagaagtaacataaaattagatcatgtt tagttatgcccgaggtcacatggtgataaaaatgaggataaactgaaattgtctgtgagccagattag tttattttatgccagtcctaggaaaaagacacatcatggtaggatacatcctttttttttttaattat actttaagttttagggtacatgtgcacagtgtgcaagttagttacatatgtatacctgtgccatgttg gagtgctgcacccattaactcttcatttaacattaggtatatctcctaatgctgtccctcccccctcc ccccaccccacaacagttcccagggtgtgatgttccccttcctgtgtccatgtgttctcattgttcca ttcccacctaagagtgagaacatgcgctgtttggttttttgtccttgcgatagtttactgagaatgat gtattccagtttcatccatgtccctacaaaggacatgaactcatcattttttctggctgcatagtatt ccatggtgtatatgtgccacattttcttaatccagtctatcattgttggacatttgggttggttccaa gtctttgctattgtgaatagagccgcaataaacatatgtgtgcacgtgtctttatagcagcatgattt atagtcctttgggtatatacccagtaatgggatggctgggtcaaatggtatttctagttctaggcccc tgaggaatcgccacactgccttccacaatgaacagacacttctcaaaagaagacatttatgcagccaa aaaacacatgaaaaaatgctcaccatcactggccatcagagacatgcaaatcaaaaccacaatgagat accatctcacaccagttagaatggcaatcattaaaaagtcaggaaacaacaggtgctggagaggatgg ggagaaataggaacacttttacactgttggtgggattgtaaactagtacattcttaacatcaatttat tcctaaaagcaatgttcatagggcacactgtaggccatagatttgcctcacaaatttaaaggcctaag ccctcaacatgcacagcagtatactcagagactatttgtaaagatgacgattctggaactttttaatg accccaatcattagcaatgattaaaattaatattcaacattctatatttaccaaggcaataaagtaga ctaatctattttaaaagggttttaaaatgaagagatgaaacaaaccaaatgattttgatttaaacttc atgaaaacataagttgcattaatcaggtgattttgttttatgagcattctgattgaagtgatcatatt tagccccgggagaataagagaaggtaaagtatgggtatggcactgaatttactgagatgattatattg tttgagttaaagaacttgtattaagaaacaagtatgtgccaaacattgtgctaggagcaagcaatgct aaaattacatgggtagaaagagagaatgaaatatctagaatgagttagaaacatcagtgttttccaat gtggagccctgacttcacatgaaaattctcattttcaaacaaggtagtttatgaaaactggactatta gcaagacagggtgggcatgccatcagtatagtacctggtgtaaaactagaaattttaatcatttgtgc tttcattttataatcagtaaaatccaaggtaggacaaacttttactttttctgtataatggactgata tttgaattatacccaactttaattttttgccagaaattatgctttattgtttctctaaaatggtacta tagatctttatttatttctatatatttatatgatttttacatatatgtgcatttacatgtatatacat ccataaactatatacatatatacacataaattacaaatatgtgtacctacgtacatatatatgcatat atcacgcaaatacaggcacattttcaatacccctttttgatttttttccttgaagagcatagcatctg aatttattatggatttatttttaatttatggtcatgttctttgagtgcttttggtgtttatctggttg ccccaaactcgctagcattgtaaagaagatgtgcaaagcctgaatctagactgactttcatattgact ttattagtcaaaaaaagtagatgaaaatgtaacagtccgtgttaaaaatgggaataagacagatgttc aagccctagcttcagcagtttttagctgagatttactggaagaaaacattttctgaactgtaaaacat gcaaaatgcctacgtgacagacttcattaacattattaaatgctatgatatagtaaaagaatttgtaa actgtcaagtgctttgtcaacattaggaatttagttattataggtatttccatatacatgttgtattt agaattccctttaattttatacttagggttgatttgtattttaactaagtcactttatatatctggtc ccattatacaagtatacttttccttaggataagaaagtgatctttatatatgtttatcaacccaaatg cccatcagtgatggactggataaagaaaaggtggcacatacacaccatggaatactatgaatccataa aaaagaacgagttcatgtcctttgaagggacatggataaagctggaagccatcatcctcagcaaacta acacaggaatggaaaaacagacaccgcattttctcactcataattgggagttgagcaatgagaacaca tggacaccgggaggggaacatcacacaccgaggcctgtcgcgaggtggggggcaaggggagggagagc attaggacaaatacctaatgcatgcggggcttaaaacctaaatgacgggttcataggtgcagcaaacc actatggcacatgtgtacctatgtaacaaatctgcacgttctgcacatgtttcccagaacttaaaatt taaaaaactttaaaaaaagaactgtagatactgatccaaaaaaaatgttcattaatgggggttaaatg attatttctaagtagactactcttgaacccttgaatctttaagaattttctttgctattgaagccatt caaactctattttattaaagctgtcgttattctagtagattttaaacagtaatacctgaatacattag aaatatccaaatctgcattacatatggcatctgcagagcagaggagtttggtcatctggactcatgct aaagtctccgaaaaatccgcttgtcttaatgatggttgactcgctaatgctatgcgtatatagtctta ttttaagtgattgaatgatgtggctaataacccctctgttagatgcactcagaacctcacctacctgg gtcctcagctctccagtgaaatctctactttaagtttattttctaacatggtaagagccttcagttta tgttatgctcaggcccgtcactgtgaataaaatattagaaatggactttttttttttgtattttttta atggatcccttggaactttaaaaaaattatttatttgagctttctactgttatcacagtgtctcctaa gcatggcctcccgttttttgttggtaatataattcttacgttattcaaattagtaaccattatttttc tcatggctagaattctggaaactattaggaaatcactgagcataattgaatggctgtttatttgaaga gctatgtcaaggcagcatagagttgtattttcttgcaggggctctggagtcaaagagcctgggttcaa accttggctccaccactttctatctgtggggcattgggcgtgttacatttgtgaaacttttgtttctc catttgtaaagtgaggtttgggggatgattaaaccagataactcatgtgaaatatttaatggaaatgt atttggtaggggatttattatttttaaatttggattgcacatgacacatgtcagggatcatgctatgc attttggatagaaagatggctaagatatcatgcctgactcttaaaaacttacctaatggtaaatgacg agttaatgggtgcagcacaccaacatggcacatgtatacgtgtgtaactaacctgcatgttgtgcaca tgaaccctaaaacttaaagtataataaaaaaaaaaacttataatcaactgtagtagaaagagatctga atggcttgccatttagctaggcacatggtatatgtgcttaattcatactagcagccactacagttgtc atgattaataatgagcttccaactgcacagaatgcttttaatccatagaaaatcaaatcagaaacaag tttttgtaaaattaatgtgaaaggagcaacaattaaaatgcaagattgacatttattttctaaattgg ttctattttctttcacatttacaaaatttataagaaaattctttatttctatgtgatataaagaacta gaatgtactttgatgtgaattattgttgccagtgctgttcaacttttatccataatttactaagcacc tacatttagacaaaggcattatccatccctttggggaggatttcagatgattcatacacagacctggt ctcgaggaatttaagattttctttggggagggaaataaggactttaaccaactcaagagtacttagag aattttctgaaaataattttatcaatgaaaacttgttatattaaaagaaactgtcattctgacttcca caaatctaggcttgaaactatggataacgagatattttctattactctcactcacgtcattttcacaa agtgaaaaggtacattttaactagtgaaagaatagaggaaatggaagtagctcgaggcagtggacgat gattcaaaaagacagggccctattatttgatcaagttatgcaacgactctgggcctgtttcttcacct ctggaaggaggaataatctccaagccctttcagactcttttggtaattcacctccagcacatcttcta aatgccagcattaactgtcctctgatttgtctcatgtttttctagccccatgctctcctgttcgccat ttaccctcatgcaaggtacaaattacacccatcatcacaagacacttgctcaagtcccattgccccct tgaagacctgccacacctactctctcaaaaaccatcatttcctgaaagtcctatacagctcatttggt atttacagtgtactgccacaagccactaagcatcgttttgtgaatacatgacttacagacttagcttg agtaaagatacttgaaaatgaacaccatttcttggctatcttcctattttgatgtacccttcaggcct atgaattttagtataatagataaccaataattatttcttggttctttcctgcacatctgaataaccct atgcaaagtgatagaatgtttttctataaggaggtcctacactggagattgtgtatttcttaatgctg ttgaaggaagagatgtgtatctaaaataaatagactctaacaaacattaatttatatttctattatct gttttgtgtattgagatatctcacaaaaataactaaacattttggcattattgatattacatatttgc catgaatatttgtaaacgaagaaaaatatatatacatcagtaattatcttggcaaactcttcaattat gcaatattgttacatagattacatatctaagtgaacactggagttttaacaatattgtgtgttcataa atgttttatttattattgccactaattcttattgccatttcaagaactatgtataagttgttctaaaa actattaaagtataggtgaccatggtcactactgcctactttggtaaaggccaaatatgtgaagactt tttaatgtgttaacaaacgttgaaggttttttaacctgttaacaatcagtaggactcttgaaattatt tcctaagagagtaaattttacaacttgcaaagcatgattaacctcttgtaattataaaccatctcttg tagttatgtagcattttgttaatgagcaaagaaccattgtggttcctttttacatttcttaaaataat tctccgtaacctcattgatatctccagtaaatttagataagcttttttttttaaaggagggttaaaat gacattttaaactaatttttcttgttagttatacagagttgaactatctgagggttttattgacagtc ataaaaaatttgttattttctgtgaaatatagagaatttaattcattatcatattattaattctgtgg gccattgtcttaattctagaggcacaagctgttttcatcccactgaaatagaggaatcaaagtatgtt ccttgctcaaagcacaaaagtgacatactacatagtatgcttcttgagtagtcgtaaatctcatgtgt taaattacatcccaaagatttcagtatgttttatgactttaataatttatggtaatttctaatctggc ctttgttgacctgtcttgctttttaaatttttagtttttcgacaaaataattaacatattttaataat cttccaaaggtgtttaaaatggcattgtatagagatagctgaaggcttttgagcttctgtgttgtaaa cactttcttaataaaacatgaattgctaccagatgatccagcaatcccactactgggcatttatccaa agaaaaggaaatcagtatctttgaagagatagctttgttcccatgtttactgcagcacttttcatact agccatgatatggaatcaacctaaacgtccatcagtggatgaattgaaaagaaaatgtggtatgaaac agaaattgctgctttaatttatattaaacacactcatattcttctcagctgttaagtattgagttata gatttaaagaattctattgtgaagactaaagtgactattaaagtaagaaattattttttccattatat ttaacttatttcatactttaatgttagcgccaatgagcaagactattgaatacaaaaactaattaagt agtggtgatagtacagtatataagggagaacattcttttagaaaggaacaataacagggagcaataga aacaatgaatgagtgtaaggtcacttagtgttaaaacagctaaaatatagtacaaataagttgcgttt taatagtgattttatataattacaccttgatgttttatttgttacaagaattgtccaggaagatttct ctaaagaccaaaggcactcttcccctaaataactccaaagccagtcctgtgtttctataaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaagtgaaaataacgtgatgaacatttttgaggaagtataaaaccaaa atactccactgcatagctgtttctgcaggtattgtattgatatattacattattcagctttggagtct ccacatccaatgttacatcatcactctaaattaaacatgtatagataaatgaaataaatgagatagca tatgaaaatctcatagcccagcccctgcactatttaaaatagaaataccaaagaattgtattcctcat ctgaaagctatttagtggtggtgtttcaaataaaaattccatctactgctgttgcttccattgtatct ttttctctgcggtactgaaagagaaagagacccagaaggggccttgtctgaagtgtccctcttttaag ctgttgctgctttaagcacagggtggacaaatgtaataggagtttcataaaggtggaataaaccagcg gattacggtgtgggtgaatactttcagatgttaaccaggagctctgcttgcatgctgggagttgccca tgcctcttctagattgaggcacattatcatgcacaacctaactccaagaaatcttttaaaccactgga aattgaacccagaacatgtctctaagccagccttttcatcctgacaccgaatcatagcatgagccagt ctgtcagggatgctgctgctctctaggcaaattttaaatgttgaaataatgaatcatgttttcttgaa aaccatgtacaccaaagaaaagttagtcattttatagatgatgaatattaacattttcttagacaatc tgataaattatcagatctcacttttggctctttttaagacagttatgcctcagaaatattaataaacc cccaagcccttatactgatcagtatgttcactactagctatgagaaattcttgaagttcttgtaatta ttgtattatttccttactttcattttattagtatgtgaataatatttttaaaaattctagtgtatgtc ttgtatatattttaacaacatgacttttaattaatgtcttgataacatttcttctagtgtatgttttc agtaacatgattattaactgtaactttaaaaacctgtggattagatgggaccattttaaaatgtttta aacctggaaaatctgatggctttaggtttagttcaagctatagatcacctgtggagaatggaactgcc aaaaaaaaaaatagctgtagcagccctttgagtattctaaaatagggatgttatccagagcattggtt tctaaagcttccattatttattgatgttgagctttcaggatttagctacaatatttactcaacatcta agccatgcttttttatcagtcatgttttatatcttttataatcaaactgcttatcactgaaaaaaata tataagtttctatgtatctggaagaattctctggtgtttcttagatatggattttgatgtgtggaata agaattcaattcaaggataacagagatgttgtcctgaaaaaaatcgaagaaaatcagcttttctttaa cattctgtcaaagctcctgactattagtttatcagcactgttttgccaaaggtgtcttctcttctctt ctttgaaaaaaatcatctgctgctgctacgccgcaagtgtgttcccgctgtgcctgagaagatgtgtg gcataaaaaaatgggcatggcctgagttaaaagtgctacatttaagccagagctggcttatttattag ttgtctaatcataggaaaatgacagagcatgcttttctcttgcaatatccgttgctgaaaattaaaca catgagcagagctttcagagaggttgactggcctctcagacagcacctcataggatggcctgtgttga agcatctcctttaaccagggtctgtccctcagcattgggttggctcacctagattggattgtcccagc agaaaaaaaaaacccaaaattcagaatcatatccaaaccggaatactctttcattcacattacttgta ctaccttttcagaaactggatacctgagtgtgtgagggtaacttagaaacttatctcatggttagaag ttttagaattagagagcgatgatcatgaaacggacttcatgatcagaagcaatggagcaaggaatgag atgtctttgaggagtatttccctgaggctgtggataacgctgacgaataatccccaccttaaaagtgg gttgaccactctagtagctgtaaggtgggagggttctttcttcagagataaatctgtgctcttcactt gcccatttcccaggttttcatgtaggtagaagaaacacctgtaatctgaagacactcttccttcagct ttgttagtgacagggatttaaatatgtctttcacacattttccttagatagttaaatttcacttttcc tgtttgtttttctctgaaggtattctaactcccctcctaatggacttctagagctttctaattctatg caatttctgttgatttgttctggtaaactttgaaggtaatctctgattcaacttcttggagattctat catgtcatctctgtttattaactttatgttactcatggtttcttgatgaggactcattaaacataatg taagtagaaaattattaactacataatatttactacgggttgttatttctgatagtagctagctgtaa gattccaattgttcttcaaatctttgtctcagtgatctctgtgtagttcttgactacttcaaataact tcctagaaggatagggatttaataatctcttaataggaacacttaacacactgctggtgggaacgtaa attagttcggtcgttgaaagcagtgtggtgatttctcaaataacttacaaaagaattaccatttgacc cagcaatcccattattgggcatatacccagaggaatagaaatcattctaccataaagacatatgcacg ttgtgtatgttcattgcaacactactcacaatagcaaagacatggattcaacttaaatgcctatcaat gaacagactgaataaagaaaatgtgctacatatacaccatggaatactatgtggccatgaaaaagaat gagatcatgtcctttgcagcgacatggatggagccagtggccattatccttagcaaacttatatggaa acagaaaaccaaatactgcgtgttctcacttataaatggaagctaaatgatgagaacatatggacaca aagaggggaataacacacactggggcctactggagggtggaacacaagtggagggagaagatcaggaa aaataattattgggtactatgtttagtacctgcgtgagaaaataatctttacaccaaacccccgcaaa atgcagttcacctgtatagcaaacctgcacgtgtacccctgaacctaatttaaaagttataaaataaa cgtatcttattttcagtacaatacaccacagagtagaagggttaaaagagattgcttctgaggaggtg agatgggggtaaggacagcacaagagcattttggggggtgatgaagctgttctgtgtcttgcctgcga tgatggctacacgactaagcccttgtcagaactcacagaactttacttcaaaaggagcggattttact acacatcaattccaataacaaatactttgtctttaagcaaagggatacctaaatatagcgtattgaat ggatctccagaaaaacacatttttcagttcatgtttcagcctaggcctcatctcatccaggaaacctt gtcttgcttgcctttacatacatgtggcaatcagtagtttcttttagggctcggactgaacactcaat gaacttcaatcttagcgcttgtcgtagcagattgacatggtttatttatatgtgtcattctctgtagt aaaaggaaaggatcaaggccattcacttttgtagtgattgtgcatggcagtatttggcacatagtaga ttattaattatggaacttctgttttcacacacacacacacacacacacacacacacacttcagagcta ttttcatttaaatatttgctttagtctccaaagcccctctgcctcaacaccaacccttctatctcatt attcatcagcttttctcctattacgaaactacttaggaaagcccacttatttagcttatgatggcaaa aataaatatttgtacttttttttttttttttagtcatcgcttcatagaacagcctctgtcctctgctt atgccatgtctgaatatatgctggaggtaaaaagagttcctggttgagagcttcaatttgagaaacta tctgagattactttccaggttccaccgtggaacctgtctgaccttgaacaaatgacctcgaacaagtg gctgaaatctcttctatttcgtcaactgtaaaatgggggaaaaccatgtctatctcatggggttcatg tgaaggttaagaaattgcttattcagtgtttagcacagtgcctgatatgcataaagctcctaggaata ttagctgttattgtatttccttaaagaagcccatagctctatatgccctttcattatatgttttagta gcccaatttaacatatggataaaatatttttaagttaaatgatttgctaatggattgttgaacgagtg gcagacacccatattatagacgaaggtcaagtccataacatacagtacatttccccactttcatttcc cattaccaaaattcattattctcctgagaaactcattatagaattcatgtcagattcatctgtgtgtt cccagcagtgccttatatccagaaataacactgagtcattgtctagatgtagcagaggtggaatcctc caaagagaagcctcagagtggccaggtttgccaagtatagggatgccttgattactggccttactctt tatgctcgtgaattcctaagttttattcctcctgtagtcatagattggcttttaagctacaagctgaa gagagagaaaacctcttccacctcgttggaatatgtctcttcaatccatttgagccaatttaggacat gagactgctcttagtctagaaccagtcatcaggagaattccaggtctgattgactcggactagcgggt caatatcagggcaaaaattccaacgcacaacacgatgtatcagtaaggagaacctcaaaattatttct taacgtccagatcatgttcctatttttatatatctattttctcacataagtcattaaaatgatgtacc tgtgcgggtcctttaatgatactcaaagatcttgaattataggctaataactaacttaataagctgca gaaattaacatttctgctacgtttatgtagcattttcccacatgtacttcagaggcttgagaaaagac cctgaaataatgactgaataacagctttactcacttaatttcaaatttgttaattcttctgggaaata ccgtcaacatccattttattatttttctcaattacatgtacgtttctacatcagtggataagttaagg agaagaattccctcatgataattttttcatgctcgaaaattttgaatcaattttttattttacattat actctttcctagtcattagaaagggagtggtggttaagataggcaagaatgctttataaggatactac tctcgtttcaattcttaacatcaaaaaccttaacagtgtgtagactataaaataaaatatctagggat cagagcattgtgctgaactttgcaggttttttagtcaataatatatatgacgtgttcacagaattctt tgtcaacaaagtacttttggagctccaggccatttaagttggtttttgtactttttctttttcttcgg aagactttttttgttctatttacctggaagtgtttcttttttggtactgtgaattaaaatgagaccaa tctactaggcaggaaaaaaccttaattagattgttgacacagacaaataagaatgtcaattagcatct actgtcacatgcctctccagactgcttctaggatgagtggcctcaagcagctacatcatctttatact cctaaagcatcaaggaaacttggagtgacaattcatatcatgaacacatccacagtgatgatgattgt gcttcttcccccccacccaacaacaaaggatgaatgccaattaatgtattcagttttttgcgtcaaag gctggatcacttgtgcaatgagggtaatcatcctgaccagacaggccatacaatccatattgtgtgaa ttaaagataatatgcgtgaaacaccttactctggatgtggttcatagcagtagcaaaaagatgaaaac tatggtatgctaacattttagagatctgtactctattttaaataattttataaaagtgcatatacaat aaaaagtgcacgtatcacaagtatatgcctcaaaatctaaagccagtcatgtaatcagcatccacttc aagaaagaaaacaaaacagtacccctggttcctctttgcaatcattagtctcccaagagtaatcaccg atctgatctgtgacagcatagattggttttgccctactatatttttgctgaattatacaatatatgct ctttaatgtctggcttcttagtgcattgtatttgtgtatcagctattctcttgtgtgtagttattaaa caatcattttatgggctgcataatattccatagggtaaatataacagttttattgataacttagctat tacaaatagtgctgttgcagacatatattctattacatgtcttttggtataagaatttacacatttca catgggtgtatacccagaactgagattgctaaatattggggcacattgtatacattttgatttagtag ataagatattgccagatatcgtaaatgcacagtttgataaatatagagatttatactttttctagaga aaagccatcaatatcagtgtatgtgtatatatatacgcgtgtgtatatatacgtatatatatacgcgt gtgtatatatacgtatatatacacacatatatatacgtatatatgtgtatatatatacgtatatatat acacatatatacatatatgtgtgtgtgtatatatatatatgaaacaactcagaagcagaaagataccc catgttctcacttataagtgaaagacaaataatgtataaacatgtacacatggacatagagtgtgtag tgataagcattggagactgaagtgtgggggtgtgcaagggaatcagtgataaattaatggctacaatg tacataatttgggtgatggatacactaaaaatccaaagttcaccactatccaacatactcacataata aaattgcacttgtaccccttacattcatacaaataaaaaattatttaaataaaaataaatatgtgtat atgtatgcatacatacatatgcatatacatatgtgtttgtgtgtgtgtatataacttacacttaaaat aagcatggatgctgcaatgaatgctcaatttacaagggttgtccatccaaacttgtggcaagtatctc acctctcaagttgttttcttttttcttcatatatttcttgcttttgtctaggaaggaataatttggct tgcctttcaagagtgtacagtcagcatgataacccaaacacttaagacacgtgctaacccatgtggat cccttgagagaaggaaaacagtggtccttttactgggcagatagagcccggggccaggtttcgtggct tgaagatttcagcttctctgcgcctctcagctcagtgcctctggaagcaatttacaacttgtgaggcc atactcaaaggccctgttattaattccccgccttccgagaccccatttcagaggatctcaattgctct cagagtgaatttactgtttcctgaattccgtaatcccaatagcaggtctgttgtcctcattagatagc ttaagttagagtcggcagtgtaattggcaactgagctactaagtatccaatgcttatgtggaaaatat gttccctattgcaaacaactgatattcatattcaatttggcaccatcatctatctataaagcagatac tacttgtgtttattaagttttatcccaaataattattttagtaataatgcttgaaaataggccttggt catttgcatgtctgtatatggcatatcctgagtctttgtatgtattagaaagatcactcgttttgact tgatggtttaataaaagatgtccctcactttgggcagagacatttgaaaaaggcactccaaccaggga cctaagaggtgaatgagatgcagctctgaatcaggtcacacggcctcaggaaggaaacatcttggttt tcacatccctcacttctcgatgtcatgtgcaatacacaaatgacccctcaacacacacacaggcacat acacaaacacacactcactcactcactgtattgtctctttccttgactaagtccttcttactaactca agctctaaagcttttttacttacctaaggtgagtgtgtgaggatttgaggtttcaatattaaaattca gaaacatttaaagttcattttaaatattagtaaaaaaaaatcttgacaaaatacaattatagacaaaa agaaaattcagaatatttggaatttaaggttgaggttacagccctatttatgaaatattagaagaaaa atgctggagagaataaagcaggtttatgagtctgatagaaagcataaccagatgattatgcatatatt tgcatatgcaaagctttctaggcaatctgaacatttaaacctacaaatgtggctgcgatgaacagcca cagaagagcaggctagaacagaagaggaggctagaacagaagagcaggcagaagttgtaaatgaaatg ttaattttcaatggttgatctcccaagtactggaacagatttgtgctgttttcaaggttttggttcaa agaatccagtagtgtattgaattgttttgtggcacttccctgttattttgctttgtaagctacctcaa tccatgaagtggctatgagccccttatacaacactgttgatttttttttccttatctacgcaaaagat ttttgattcagggccaggcatggtggctcacgcctgtaatcccagcactttgggaggccgaggcaggc ggatcatgaggtcaggagatagagaccatcctggctaacacggtgaaaacccacctctactacaaata caaaaaatcagccgggcgtagtggcatgtgccggtagtcccagctactcgggaggctgaggcaggaga atcacttgaacccggtagccgagatcctgccactccactccagcctgggcgacagagccagactccat ctcaaaaaaagaaaaaaaaaaaagattttttattcaggtggctatcagactcattaaatagaagcctt aggttaagttcacgggttgctagttggaagcctccatggactatgttcataaaataatagaaaggagt tatgcaggacttcttgaaatgttatttaaaaagtcagaataggctttctattacttgtctgaggtcaa atacatgtagtgctttctgaccatttcatccagggtgttagctaggacaataagaggtgcttaaaaat tattagattgagtaaatgagaaagcccttagaaacataggaacagaatgacccttgctttggatctaa tattgactcccacgcctaaatccctttggagaactcctttattttctcttccatcaagagcaggtata aattaaaaacaccattaaaggggccatctagctcagctgaagctttcatcacacatgtaggggaggta tggttgggagggatctttttatcctttaggtcttcaatttacataggacttttgaataatcaaatagc cccaaagagctgatcttaggactagttgtaattgagactatttctccatggggtagaaaaatctagtt gtaggaaaactgagaagtagatgtatgttaacctcaaaggctgttttttacaaaggatgttaaagcat catctttgctcagaaagggagcaataaaacaaatgagtggaaataacaaaaggaaataatggccaggt gcagtgcctcacactagtaatcccaacactggggggctgtggtgtaaggatcgcttgaggctagcagt tcaagaccagcctgagtaaaataggcctcatctctacaaaatagatagatagatagatagatagatag atagatagatagatagatagccgggcgaggtagtgtgcccctgtagccccagctactcaggaggctga gatgggagaatcgtttgagcccatgaggtcaagtctatggtgagctgtgctccctcctgccactgcac tccagcctgggtgacagagtgagatcctgtctcgaaaacaaaaggcatactttttagatgtaatggaa tagagtacttccaaacctggctgcctgctggagttgtattggaagaggttgcacgacttcagtggaga tggcctagatgcctgctcagcagtcatctagttaaagcaactaagaacatgtaatatgaaactgcaaa aagagatcgtgtacgtaaaatcactctgggctcctcagatagagtaataaacacaactcctgacagcc aaataaaaagagaaataatacagcccttgacttccttggttgctttgacatactaagtaggtgttaca ggttgggttctctgggaaacagactctaaaacatttttatttttactttatttgttgttattattatt attattattattttagacagaattttgctctcgttgtccatgttggagtgtaatggcacaatctcgtc tcactgtaatttccgccttatgggttcaagtgattcttctgcctcaaactcccaagtatctgggatta caggcaagtactaccacgcctggctaattttgtatttttagtagagacggggtttcatcatgttggtc aggctggtctcaaacacccgacctcaggtgatccacccacttctgcctcccaaagtgctgggattaca ggcgtgagccactacgcccggccagactctaaaataaagtttaatatgcagaatacttatcagggaat gcccactggaccaatacatattcaagagagggcttagaagcaggattggacagaaagagaagttgagc tgtaatgcaggcccaataacagccttagtgttaagcaggctgagagattcagcagttaatgagacagt caacccaaacagttttataggcatcaaaagtatgatcagcatggtgtcagtttcctgtgtcacttgtc ccacagtatgataccaaaattaaagagaccagatgacatgcaacacaagcagtgtgcactctgttgtt gagaagccaatttcgtcatgcaattaagcagttttatactctgcagctgtactttaaggggagctgag atggaacatcatatgtctcaccataaccagaaaggcagatgagaaatgttctatcgccacctcccaca aggtaagggacttccctaaagatacagaggtgggtggaatattgccttggtagacttcctctcaagac tgcctatcttcccatgttggaaggatcacagagcatttgtcaagacgtgggtcaatctgcagttgaac tttgtgtatgtggcctatgtggatacttataatatcattgggcacctccatagagctgtttcccaatt gaccaaacatatgggaagcttcagagcttcgaatgacccttcagagtagtcctgagaacagtgagcct tactactcctgcattaatcagtcattggatgatagccttctcagaaataagtcatgaccttgtgcaag ggggctcttcatggctgggaccacccctaaaactgagagctgaaggctgtctgccaccagcccttcca cctgctgggacaagttctttattgaagggaaatctgagtagttcatcagcgtccatcacagtagtcaa gccgttcattcttccttcttatgacaacattgtgcttattgttatgtaatccctttccagaacatttt aggttaagttttaaaaataatgcatataaatagacaattcaaatactggggaaaaaaagcttgcactt atattgttatagaaatgtgcacacttaaagagctgatttcttctgggtatttacataactttatttaa aaatccatccatttttaattagctgtttttaatatgcagttagctaagatattataagccatatatta ggctaatggacatttaacagcttagttaagttcttttaatggaaatgctgacaaacctttgtctgtaa ttatagcaacactgtgattacagaaggaggtgcctctccttgttgtttgcagccctaaaattccatgt ggctataagtaacaaagtccattattagataaacacaagtcatacttggcattacttgcattactcgt ctccttgctttatttgaatcattttttaaagttgtaaaatgtttttcaaaactcagaatagtggccag ttaataatatgattcctcttatattatgagattttaaaaaatagttcaccagtttctggtggcctcta tacccattggcaagtcctagccattgtgaattaagtaaacaattctttatggaaattttttaatcctt aaaccctataagtttttattcatcatgtcaggtcacttgtcaaagggtttaacattcagaattcaaca aaagtttatcaaacacctattacaggacgtgcaattttgggcgcactgggatttcagcaattaacaat caagatatgatttgtatcgacatggatattacattctctcacaggagacagaaaacaaaataactaga aaatatacataaagagactttaaaatggggtaaaattacagattgtgacaggatgaccactttggttc agaatatctaggacatttttttctttttttttcccctccctccctctttcttttttttctttttcttt tggtgcaatctcagctcactgcaacctctgcctcccatgttcaagcttttcgtgtgcctccgcctccc aaataactgggactagaggcatgcaccaccaggcccagctgatttttgtatttttagtagagatgggg tttgaccatgttgcccaggctggtctcaaacttctgacctcaagcgatccacccgcctcagcctccca aagtgctgggatttacaggcgtgacccaccaggcccaagcaaggacatttttttctgagccatgttat ttaaacagagatctgaatgacaagaaggggccagctctgtgatgtaggggaagaaaaatatgttcctt ctacccttctaggctgcccagctggagtcctacaaagttagagtgacaaaagacagattaacaagagg aaaagcctagaagtttattaaaatattcagtgcacatacacctggtagaaactcagtgatgagtaact caaaggggtggttagaatgttgggtttatatagcatctgaacaaagaacagtaaacttgtagagaaat gacaaaacaaagaaaaaaggggtttaggtatttagggttgccaaactgtaggaaggtaaatatatggg agaaacatggagtatagtttgtttatgccaagtctatcttgagatcaacttttcgtattcttcatggc cataacaatttcccaggagagagggcttatagcagttatcatttctcagaagtttctgcttttattta gacaagggaagcactgggaaggcttctttttgcttatattgattcttacttgcctctaactaaaagta atctttatgtcaaagtgccatattttggagtggtatatattgatctcctataataacaatcaaaagga acagtattctaggcaggagtaccactaatgcatagtgtttggtgtaaagacaagttaacatattcatg gggcaacaacaacaataagccaatatggctaagacattgaggatgagtgagttggagaagtaggcaat ggccagctcatataaagacttgttcgtttttataaattgtttagattttattgtaattatggtggcaa gtgattggagagtattagcttcactttgactggcttatcgaaaacggaatgtagggggtgaaagtgga ataaaaagaccagtcattaattgagtagtccgtgtgagagatgatagtggcttggacaaggacgattg tactggagagattgaagcgactgatttcagatttgtagtcaacaaggcttaattggtaggagaaaaaa ataaatcagtgttaactctttaatgtttaacttgaataattatgatgagggtattaccatttattgag atgtagaatattataaagtaagagcagatttgttcaaaaagtatcaagaatctttatttggacatgct agtttggggatgcttattagagaccctaggaaactgaatataaatgtggattttagagaagagcttag ggctggcagatgcacattaaggatctgtctagagccatggcgctagagacctccaggagaacataaat agtctcaagatcaagccctgagacactcagatgtttagaagtggaacagaagagggacatccaatata gaataccaagaattaggaggggaatcaagagagtgtggcaatatgaaagatacaaaaagagtgttgaa gggagggagtaattaataaccagcatgttatgaggggctcagtataatgaaaagataagtgactattg gatttcgcaacatataattttttggtgatctggacaagagcaatttgaacagaatgatggatatggaa ggtccagaggagtaggctgagtaaataatataaggtgggaaaatagatacaaagattatagacaactt tttcaagaagttttactgtgaaggggcacagcaagctgagacagtgaggataaataatagactcaagg atggtaactttagaataagaaatttcaatctgatgggatttaagtgttagcaaggaagctttaagaag ttattttccccattagaatgatctgaaaaatgttttagaacattcctcttatattctattttatcaca tttatataactttcagagaattgaaagaggtattaagttattatgaaattttctgagattaataagat aacaattataggatgttttcttttagttgaaatacacctactcagcctaatttttataacttcttact gaagtataatatacttcagtagaaaagcatgcctaatataaaggtgcagctagatgaatttgcacaaa ctgaacacatccctttaaccagcacttagattaaaaacagaaccttgatgatacctcagaggccccct tctgccccttttcagtctctccgtgctacccccatggataagcattatcgtgatttctaataccatag attaattttgccagtttttgaattttatgcaaatggatctatttcacctaattgtaaatatataacat tgtcatagcaaggcactcattgccttacactgaaaattacattgactctttgccacaagcttagactt gctttctcattttattatcatcaagcctatagctttcacactataccttgttcctgctcttccctact ctatttcttggtagatattctatatcagtcttagagtgcagtttgcagaacccctccatcagaatctc ctagggagcttgttaataatgcagattcctaggcccctcccatggtttatgaatctgagagtgaggca gacaagactataccctctcatgcctctataatgtaataatgtcttcctagaatgttctttgctgcatc tcttattaaagaaatcttatgggccgggcagggtggctcacgcctgtaatcccagcactttgggagcc tgaggcgggcggatcacatggtcaagagatcgagaccatcctggctaacacggtgaaaccccatctct actaaaaatataaaaaattagccgggcgtgctggcaggcgcctgtagtcccagctactcgggaggctg aggcaggaaaatggtgtgaacccgggaggtggagcttgcagtgagctgagatcacgacactccactcc agcctgggtgacagagcgagactctgtctcaaaaaaaaaaaaaagaaagaaagaaaaaaagaagtctt atgtttcctttatggccagagcacaacattgtcatgaagtcatctaaaatttcccactagaggtaaca tctccttcccctgtctagctcttttaaagcattacctccatttgccttgtatcatagctgcttgtaca cctgtctgtctttccgctgaggttataatcctctggagggtcatgactttgcattcctttgtgtctcc cattagcagccagcacagtgccttgcatactgttagttctaaataacttctctctctctctctctctc tttttttttttttttttttttttttttttttttttgagacagagtctcgttctgtcacccaggctgga gtgcagtgcaatggcatggtcacagctcactgcaacctccccatcgtgggctcaaatgattctcctgc ctctgtcttccagtagctgggattataagtgtctgccaccacgcctggctaatttttgtatctttagt ggagacggggtttcaccatgttgcccaggctggtctcgaactcctggtctcaagcagtctgccctact cggcctcccaaagtgctgagattacaggcgtcagctgctgcgcgcatccctaaataaacttttttttt tttggcatgaaatctgtaacactggaaagatgttattgccttagaataattaagagattaaatgtaga atctcaaaaacattcatttttttccatgaaaactttaccaggcctcaagggataggaaaattatgggt acagaattgagaatctgtaggaacttgcaagataaacaacggtttcacaagaaagaccttgttggaga gttaaattttcagacagttgtaataacttcacattaaagttttgtcaaaaaataagtatctgcatgtt ttgtttgccttccaatgccctcattttatttgattttttcccataagtaactatagtgaaagcacgaa aatgtgtttctgtgtttgtgtgcctgtatgttaattgtgactgtttctattgcattgttattgcagaa cctaggcacgcactctgtaggcttgggtgctttctccaactgaaaaaaatcctacatatggataaatt atttttacagccagtctttaattttacaagtggtccccctccttctgtttttaggatggcagagagaa tacatatttacttaccattatcacttactcatgctttgagcttgaaggaaatgagacagaaaaatgaa gtaacattaacttctctctggaactatgtttctcatattagagctttatctgaggagttcacttcctc tctcttcaatgctttgttcctctccagtcgattcaaatgtcctcttaaagcagaagttccgaacctct ttctgtgacttcaggagagcatgagaatgtaaatataagttttaggactaaattttcaaagacttttt ccactcagctctcttttcctcttcggtttgttgttgtcgttgttgttgttgtcgttgttgttgttgct gctgctgctgctgtttttccccttccacttccgtaactgagctcttagggtccatctggaatctgatt gcaattaaaaaaaaaaaagtttatttttacctccttgtacgtgctttctcctaaagcaggagtcagaa gccttttttctttgaagggctagttagtaaatattttaggcttgtcgtctttgtcgcaattactcaac tacgctgttgtagtatgaaagcagacaatacatacctgaatgagcatggttttgttcctagcaaactt tacgcacagagaaatttggatatcgtataatttttatgtgttgcaaagttgtattattcttttgattt ctccccaaccatttaatatgtaaatcccattcttagcttgtgtgccatacgcacacaggcagcaaatg cgagttgtcacacaggctatagtttctgactttatgtcttaaagtaaacagtaataatcattctcttt ttccaaacagtccactaatctccctttgtattcagcccttgcatagtaaacgccgtttcttcatcatc ctgatttttattctgagaaaatactgtatattgttcccatgcactagggttcggggaaatttaaaagg atgtaggatctccttttcattggtcctaaaattgcactggggaggcaggtcatgtttatgaacagata aatagtatcataatataatcatgcatttctatggctagcatttagaactatagcttttgatgtcatgt ggtttttatatggttgattatttttttcttatttataaaatgaaaaagtttgagaatttttcatctcc ttaatgtattcccttatttgagggaaaagtatttacctactacataggaatttatcttaaaattttct ttgtctatctatttttatggaatataatcgagcaactattttactaattaatactttaatatcattat gaaaatgttctcatatttttaaccttataagatcagataattgctatgccaatctatggttgaaatgg gttcttatacttaacgctatgctctttcttctgagatgtaaaaatatgtttaaatcagaatttatata ggtgtcaattcaaaatgacagtagttcattattttgattagtataaatgttcacaactaattctattc tcttatctattaagtcaccaaataaagtatatttgttttaaatatttaacagtttaaattattctttg aaaacttatgagtctaaagtaagaacaattaacccattcattttgcaagtgggatagttgaattttac ttgcaatccagggatttttgacagtttgaaatatacatacataccatgtatgtttaggaaaacattta aaaagagggggttgtaaaataataatagttcttccatgattttttagccataatgtttataatataaa atatgtatactcttgttattgaatgtagtatgtttctaatttaccagaaggcaagagaataatcctgg agaatttctcaaggcatcttcgaactctttgatttattgctcacatatagtaatttgccaaatgacgc cctagtgaactgaaagaattaatgccccgtcctaagtcactttcaccgagggactgaaaacctgcagc attttgccaattagaggaggaaacaatctaccttgcagagtcaggagtactggataaaggagctaaga tgaagtagtaagtacgtttttgcaacatacgaatttagcagactggccttgtgtttatttttggccgg aaccattacacttatttccaaccctctcctttatttgttggttgataatgggctaattttgaatcttt actgtcaaaagaacattaagagaagcagccctgcctgcatcgcaggctatgtctgtcctttgccgagt attaaacactaaaaaaaaattaagaaaatactaacaaaatgacaaagcattaagaaaataaaactaga tgttaaaggaaatgagaaaataggaaaggatgctgtacctggagtgattttttttccccaggctacct aagatgatcaaaaaagagctaatttctcttaggtttctattaaggaattactagaatatcgggcacac caggaaactttatcagtggacctgtcctgaaccaaattttcttaatgtatatatgataatttgttacc acatcccagattattttacaggaattaaaatatatttgaaacactgacagggaaaattgggtaagaca ttgatagatactacaatctgtacttgaaactgcactcaaggaattcgttagtcaagaaagaacacaat gactgtgggcccctctgggttttggaacctcttttgtaaagcatttttttttttcccaaatagaagat attatttttgaaaaggttaaataaaaaatctttgttcactatatagtttcctcctaaggagtaaatta atttatataaaatattgcaatataaataacaattttaaaatctcaaaagagcagtgttttaaaaataa tgtagaaacattaagaaatgacttcaaatgataagaatgtcattggagagcaaagggtttttaatatt acatatcgtggcacgtatatcagcacccaaccgctcaagatacagagttctttacaaaaatcaaacag aaggaaatgtgccaccttgttcataaactatatttaataataagccaggcagataaagtcactttcac aaataatgagcaagcccatggtaatataattcatttacaataagatttatctcatggaattcttagac tgtgctttgaaatttaaataattctgataaatgccaacagaatagagaaatcaattccagagcaatta ctaacacgttgcattacctttctaacattaatatttctcttcatacatatcattgaagagaaaatgag gatggaaaataaaaagatcaggtaatatatttgctttctcatctagggttgttatgatcttcaagatg aagttttattttttactcctagcaaatgatattcttttttattttagtttttattattttatttttct gtaaattattggggtacaggtggtatttggttacatgagtaagttcttttttttgatatttctgagat tttttttttattctactttaagttttagggtacatgtgcacaacgtgcaggtttgttacgtatgtata catgtgccatgttggtgtgctgcacccattaactcgtcatttagcattaggtatatctcctaatgcta tccctcccccctccccccaccccacaacaggccccggtgtgtgatgttccccttcctgtgtccatgtg ttctcattgttcaattcccacctatgagcgagaacatgcggtgtttggttttttgtccttgcgatagt ttgctgagaaaaccacgaggtaccatctcacgccagttagaatggcgatcattaaaaatcaggaaaca acaggtgctggtgaggatgtggagaaacaggaacacttttacactgttggtgggactgtaaactagtt caaccattgtggaagtcagtgtggcgattcctcaggcatctagaactagaattaccatttgacccagc catcccattactgggtatatacccaaaggattataaatcatgctgctgtaaagacacatgcacatgta tgtttattgcggcactattcacaatagcaaagacttggaaccaacccaaatgtccgacaatgatagac tggattaagaaaatgtggcacatatacaccatggaatactgtgcagccataaaaaaggatgagttcac gtcctttgtagggacatggatgaagctggaaaccatcattctcagcaaactattgcaatgagtaagtt ctttagtggtaatttgtgagatcctggtgcacccatcacacgagtagtatacactgcaccatatatgt tatcttttgtccctcggcaccccttttctaccccccaagtctccaaagcccattgtatcattcttatg cctttgcatcctcatagcttagctcccacgtatcagtgagaacatatgctgtttggttttccattcct gagttacttcacttacaatgatagtctccaatcgcatccaggtcattgcaaatgctgttaattcattc ctttttatggctgagtagtattcatatatatatatatagacacacgtacatacatatgtatatatacc gcagtttctttatctacttgtcgattgatgggcatttgggttgatacttgcacacacatgtttatagc agcataattcacaattgcaagtgatattctcaggaagcatgatgtaagtgacagagacttactttgta gactgcactcattcacttgttctctgaatgtgctctaggcagcctgagtttctactatgtcagtgtta catagatgagaaaccccatgggtggtttccacagaggctgcaatactatttttgataccaaaaatctg tttggttttgtgagccccagatgcccatatggaaaactgaagtgttgatacctctttgtagccctctg atgaactgcatggttcaccttcctcagcagtttgagcggggtggggagagcgcctgcttcctagccat ccgattggcctgaatcatcaaaaatgctatcatgaaacaggttctgtttatctgctccagattacacc catcatgttctagagtgctggtttcatgcttgaatctagatcaagcctgctttcctcccctgcctgta ctccctgtggctacctacagtcctgctgctgacagataatctaaaccaatagcacctaattagcctat acgttgctgatggtttaatttctggaatgcaggtaatgaatgtgtttttgcttatccaagtcttccca tcagatgtcaaatatagaagaacagtgttcagaggtcctaaatttaaattggagtgagaaattcacag cgcccctgaactcaggcaaaatgcactctgacaagtcaaccagatattcacagatggtctggaggatt tgaagcctaatttggtgaaataaaattaaatgagtgaaattgtatgcagtcattaatctatcaccata cttaaaatgcttcattgaaatttcttttactgcttcaaatgaaaaaagatcaaactatgttatagaaa agcattcaaaacccttacataacatagataaaacttggttggagacttacagaactttctctgctgct tcgagaaagttacagtgcccacaaatctattgctattagaatattttattgtattcaacactcaattc taccataattatgtatatgagaaaaatatttttacctataaaataattattattaccttttaaaaatc tgacattcttccttttttctaaagaaacatatttagatttagcttttattttatttttgtgttgatac atagagattgtacatatttctaagattctagtgatattttgatacaagcgtataatgtgtaatgatca aatcagggtaattgggatatccaccatctgaaacacttatcatttcttcttttcaatgccatcatacc aaaaggaagtaaatagaatttcaaatataaggacagccatgattttacatacatgcctacgattccac cacaaaccataattacgtcccccaaacttttaacatttcagatactttgtcccaggtatttcatgata aggattgggctatgactctgttacagaagggccaaatgactaaaatgtctctgaacaatattgattgc aaatattctacccagttgtcaggtcaatatgttccaattcggaatttataacattgtatctctactcc caaaccatccaatctcacctacctcacttccatattatggtgggtgatctcagattatatttaagctc atggttacttgtcaagtagatatggagtttagcctaacttttgaaatttatgctgagattacccttct cattatagaattaagtaggcagtttccaagtttagatttagcaggcagtttttttcaaatcacttaaa agttatatttttttagggcattgaacaggtttgaaatcctaccaagatgtcatgtacacatagaccaa tagaacagaatagagaacacataaataaaactgcacagctacagccaactgttcgtcgacaaagtcaa caaaaaaataagcattgggaaatggattaaagatttaaatgtaagacttcaagctataagaatcctag aataaaatctgggaaataccattctggacattggcttgggaaagaatttttgactaagtccttaaaag caattgcaaaaaaaaaaaaaaaaaaaaaatgacaagcaaggacttactaaaataaagagcttctgcat ggcaaaataaatgatcaacagagtaaacagacaaacaccaaatgggagaaaacttttgcaagttatgc atctgacggtggtgtaatatccagaatctatgaggaacctaaacaattgaacaaacaaaaatcataaa acatcatttaaaaaatgggcaaaagacatgaacagacatttctcaaaagaagatatacacgcagccaa taaacatgaaaaatgcgtcacatcactcatcatcagagaaatgcaaatcaaaaccgcaaggagatacc atctcacacccgtcagactggctttgttaaaaagtcaaaagacacccaatgctggcaaggccgcagag acaaggggatgcttatacactgttgttgggaatgttaattagttcagccactgtagaaagcagtttgg acatttctcaaagaacttaaaatagaactatcatttgacccatcaatcccattactgagtagatatcc aaaagaaaacaaatggttctaccaaaaagacacatgcactcacatgtttgtcacagcactatgcacaa tagcaaagtaatgggatcaacataggtgtccgtcaacgttggattggataaagtaaatgttgtacaca tacaccataaaatactatacagccacgaaaagaagaaaatcatatcctttgcagcaacatagatgcag ctagaggccattatcctaagcaaattaacataagaacagaaaaccaaatactatatgtactcagttat gagttggagctaaatgttaggtacttatagaattgaagatggcaacagtagaaactagggactaatag aaggggaaaggaaagggggagacaagggttgaaaagctgcctattgtgtactatgcttactacctggt taatgggatcatttgtatcccaaacctcagcatcacgccatatatccaggtaacaaacctgaacatgt accctctggatcttaaaagttgaaaaaaaaagatgtcatataaatattcgtggtcactaaaagtatct aatgtattatacataaaaataaaaattgggtgaattggaagtgtattctttgtatcaagtcatgtcgg agatcctattctgctttgatcacagtgtgaattcttttgcatttttgttaccagtcacttctttattt attgaactaataattacatattctgataatctgtcagaaagataaaaacattctttgtccatgtgtct gaaaatttttaacctatttttctaatgttttaagtgagaagagcatgttaatactgaaattgtaagca gtagactgaaaaatcatcccaatccatgggttatatattgaattgcttttaactgtattactaaatat taagcttaatttattttatttctacatatccccatttccactataggtgatttgtatgaatttaggaa cttccttctctcatccatttttatattaaaactcagactttctaaaacaatatttctatccatccatc gttggtaactatgtactgacatgttttgtgcatccgaaaaatgttagcattagtttgtgcgcacagaa gtaattccagtcaccatatgatgagctgatttatttatttcgtaagtgtgttcattattattatctct tcagcacccaaatatataggggacttaatgatacctacaagtaaaaacggaagacaaaaacgccctgc tctctacagaggttaaaatgtttttgcaacagggctctagatctcagctgtgaaagtagggacgagat gaggctaggcatgcagtgtcagtataatacaatataatcaacatgtcagcatctaatgcaggtgttgc aaaacaaaatgtacacatgggtagtcaggtaacagaaaagcatgaagtagtaagggctatctatgcaa gaggttccaagctgactatatactgaaatatttaaacactatgtggggcaaataaaatggacattaga acagttcgatggtcagttggggacttctgctctttcttccagtctctgaacatatcttaaagccacaa tcatctatttttatttattgttatacatttatttataagccagcacccctgtgatttaagttctgttg aaatgctgagttggaaaagatcgatggatgggggaaatttagtgcagaggttttgccccaggttcaaa atcctttataaaatattaatacatggaacaaatattgaacaattaaaccactgataagttaatcaatc tgattcaaagtacacctgtgaagagggacatggcaagaaaaatattacagtaagaactagaaacattc cttcatggctgcttgatatggatatgtcatgtttaagaaaattcttctttagactgttgagatttttt ttcctgacaaagaagattcactgtcgaggaaagaaagaggtactgtgaaatttgttattgaaaacatg cacatacttttgtcagaatgagttaaagagtgaacaaaatgtgcctattacttacgtgttgtgctgtt ttaattcaagattaaaatatttaacgtccacagacaagaccacttttatatgaatattatttttctgc tttattgctcaattttattaccatttcaaaacacccgtgttgctttctatggccaaagatgtttagca cttttcatggttatacttctgtacagtccaaaatacaacacttactttacacatacacaaacatccaa tgtattttgttttctgtcaagtaaagacaatgtctgtgttattaagttaaatgtcactttcaaataca ggatatgttgatattagaatgttcaactttatttcctcatttaagcaaattacagtgtgaagaatgta actgcagcaatttataaaaatcatatcacattcaattatgagagcaaacttgttttgtagacttgaac tagtttcaattaatcttggagttatcatttcaaaaattctaaacagagagaaatacggagtgtaataa tggtaggtctttgggtaagctgcttccaggaaaagaaagcaattatatatgttcacatagcactgaca aggagaaacaaaactttggacggcaaagaacttgcattagtctttttgacatgttcctgtggtgtgat ttattacgtagacaatcagctcaacttctcaagtttgatatccttggaatcatttgaaatttaaattt taatgaaaattcattaattccaaggccaaaagaagtgattctaattgcttttgagaatcagactatga aagaattctttggcaaacttgcactgtcttttctcttttatcattggttgcttcgtaggtacttaatt gaaggtcctctgattatcagcacgggctgacatcagttcactccatgcattttaaacagtaggccaga tgtttaaaggatcagctgaagcatcgatagcatgctagggtgaataataaaattttcattatctacaa gaagcaaataaaaagcataagcattttcccccattatcctgaaggagaagatgaatgcctaagcaaca ttttaagaatgggttgagtgtggcctgtgggaaaatttgggtagaaaacttgtagttagctaatgtat atactgtttgcctctttagctcaccatatacccacacacatgggcatgcatgcatacagacagacaca tacaatacacacaacaaacaggaaattcagatatactgaagaaatgtatttaagggattactaagttt ttgtaaataaaatcctttaagatgctgagaaacaatggaagagaagtaggacatgatggctcatactt tcgtaatttacttgtttaacgtttgccaaggtttaaattaatgtagatgtttttgtggctaggattaa tgatctaacagtttggaataattaggcacttttatcacctagaaagcccagaaacccagcatgcaaaa attctggtatgtctgcattttacacttagatataacagagaaatgacaagtagtcaagtggatagaga aacgaatgattcttcacacatgcacacacacatagaaattgtctttttaatagtattttaatgtaaca catttatgcataatttctccatagtgtttatcttatagtgaatatgtgatgaatagtctctaacatta gtggttttatagattaaacataattaaggctttatatattaaagagtcaattggtgacattctaatat aaacatgtttatctcatatacattgaaatattagataattcattcgttgagaataaatcgaatgagtc aaaacttttaacctccactttgagctttgtaatagtatccactgaaaatattcatgaaaatttttaag tcatttctatttatatattcagtccaaacatctcacaagtttaaaatgtaaactcaagaatataattt ctgtattctacaattggaagcatccatcatatcagatgaacttatatagtttgtgaaattttgcaaac tttctgtttagtaaatcttaatgtcaaacattttaacttccaggttgtctttcttttcagttttaata tccgcgatctttgtatactcgttgaatggattctcaataagtaacccacaaatatatatacatactat gtacctacaaaaaataataaaaagtaaagaaatcgacacttatccatacctgtcccatagtaataaac tattcataagtatatttgaaagatatgagaatcataaaagttcgtgtttgcacccttttgtgcgtgga atcctaggtttgcattttgtggatctagactttttggagtgtggaaataaatgaaacaaataatcgag acccagtcttatattcaggttatcattttactacataaagcataaataacatttgcagtttgtttcta tggctagctctaaagtcttagcaacgagaacattatagaaagacttcaactgtagcttccagcagaac ttctgaggttccgtttatggactaagcagcagttgagggggacaaaactcataggcaattgatcactc caaaggatagattgtcttttctaacctaatcaaaagatttatagtgaaggcatattcagattttgttg aaggatatggatatataatcatgtgtgtgtgtgtgtgtgtgtgtgtgttagacatacttaaaacatta tttgagtagaaaattctgcacaaatggaaaagtataacatgtgttatatccacacatgttgagcattt acctggctgaaacatcaaaagctgaattgacttaattgaatgttgaatacttaatagttactttgtag tgactcactattaaaacattatctcaagctttgtcagaattaatttttttaaaaaactcagattagtg tcaggtttactgaaacagcagatctgaaattactgtgtttttttttcctttcaataatcagtttctaa tccaaaattgaatatcagttccaactctacattcagtttctgttttacttgtttggactggcttttgg ttctgttttccacatagatcctctctgtgtaagacaaagccatttgtgcagattaaattttactgagc gtgttaacctatttaaaacattcatccaaaaagactagtatgaattcttcatatggcaagctgcttgt tttaaaacttccatttattctaaaatcctttttacttatactttttaagaaacgtattcccgatatac aaaagtaacacatgctcattaaaacaaattaaaaatagtattgtataaagagctgatacatttctgcc ttgccccatttaactttcttaagtgttcatgtgaatcatccattcacatcaagacatttatctgtatt catatgaacgtgttttaatatatataacatatatagaattttatataaactttccttttaaaatagaa atgaaattatatgatatatttattctgtgtctagctcttgtcacgtaattattcaagaacatatttct aggttaatatctgtattcttaggtagcattcactaactcctcatctacttgttttcttccattctaat tgtgtttaacatttcttcatacaattggttgtcatttggtcttcrttcatggagggtgcataatgttc attctcaccaattctttacactttacataactgcttgatacgaagccagaccttataaatatcaacaa agcaggaacactgtaatcagctatcagtttcagttgagctgaatgaccctgaatatgtgtacacatat tttccaggagattttaaaactgacacctcagatttctaagacctggagaaatcagcatgagaaacatt gatctatattattccgtgaaatgatttcactaaatagtgaagcatctcccacatgtggactctgtaat ttattagaataaagagttcatgtgcttctgaagaacttgaactactcttctggcctccgtacattggt ttcttagctataggaaggctgagcatgtttttcctatgcgtttcctttctagctcatcattttagtga caaaacaatctttcgtggtgttgctctagctatagaattgtttcagattcatttgaccaaaggtggca aatacaacagtcccaacaaaaacaaaagacctattacagaatgatggaaatgaccccagggaacaatg gcacctccacatttcttaattccaaggttataagcagtggtgtggacaattctcaattccaatgctga atcgccttctaatttcaaatacctgtgctaaaaattatttacgtctactgaaataatgaactggaccc caccaggaatggccgatatgcttgtagtcagagcacaactgtagaaagaaaataacattttaatttat agaggtatgatgatagctgtttcatactgttttcagaacgatgaatggcctgctcagtagtttcttgt catcgtactgagacactttaatttcttaccagctgagatgaggaatacgagcccagtgtgcaggtgaa attgcttaacaggagccattaaaatttggaagagtcagaatagcatcaatcaaaatgctttcagtgta ggaagtaaacatgtactagcctgacccacctgtcttttcttttaggtatgttggtaatattacaatca ttttgaggtatccataaacaactgcttagatctgaagaattgtatatctttctttactctgccctggc ctggggttatggttctcattgagctctaacctttcagaaaaaaaatgtagagaagtggttcaagaaga atgctttatcttgcttcataaaaatgatagtgatagttttattgaaggcttactatgtgccaggccaa agtgcgttttattatcgttcccattttccaggcaaagaagctggagcacagagaggctaagtgagttg tccaggatggctcagctaacatgctgcagttgggatttgcacccagaccaacttcttttcaaccactg tcccatcctgtgtcttctctactcaaaaagtgtttcagctccaaacctgaaactttaaagaaaaggaa atccttagtggaaagactaggttttagtcacaaattatctccttccttacattatttgtctctttttc aaatactccaagctttgattaaaactgtctatcactaggaacattgtagaattgctaaggtggaattg ttaaaagaactcaattccaattaactttgccattgattactgtgtgttctggaggggtgttctttctt tcaggttaatgatgctttattgtatatctcaaagattaaaaataacaatgaaggaagtagcaaaccgg aacttctctcacaatgcatctttcaatctcgtgctttaaatgaagataaaatcatggctgtggtaagg ttgcaggaaggatgatatagattaagtttcttgcaaactgccctctgaattttcaatagctgtagaag gtattggttttccaaaaaattgacaaattgaggattcattcagcagtttttttctaggtctcttacca gaaagtgatcactaaaaagtgtagggaaaccactcaaagttggatagatcattattttcacttaagca ttttaatttcttgaaggagctttataatgcaacaaagaatttacagtcctgtgtcaccgcttaaattt tctagggtcatcagtaaactcagtggaaataaattagttcatgaatataattgacccttaaattctgt cactgtgcaagtaatcggtgggtctgctggatatggctttcgagcagacaggtcaacttcttcaaaca gagaagaagcatagcataaattgaagacaaataacaaactacttgtttcctccttctttggcatcacc ctatggatggagtatgcatttataatttaacacaatcaagagatctttattatcctacttttgggtac aactgcttcgtttctcttttgaatctctacagctatttaaaaatctgttttgtaaaattctttaaaaa actaaaacatcagattcatatttcaggtatcttactatcttataccaacttaagcatccagtattatc acccacccttcccctgagtgaatccttagcactgggctcttcctgttttatccctgtgcatgctgagc tctttctggccttcaagtctacttccgttgcaactgttgtctgaatggtctctctatgtccttcttac tctctaaatatttcggaatttaaagcctggaataatctaccttagtccaaaagatatgctacactatt ctagttcacaatgatctcacactgccgttgatacacaacatttaatatcaacttaatatctatttcag ttcattacgaggtcacttatgctacatcttatattgttgccttggacttttattatctcttcatatat gtgtttatggtgctcccaccctcacgagaagttgcaaataccatgttagctgtctgatggctttctat gttgtcaggtataccatttcccaaccagttggcattcaatgattaagttcattaacaaagaattgtat gtgttgaaaaagatgtttttttcttaatgaagcacttgtttttatttttttaatgaaatccaccctct taataaattttaagtgcacaatacagtattgttaaatataagcaaaatgttgcatagcagatctttat aatttttttaaccctacatgcctgatagtctatacccattgcacagcatctcaccatttcttccctcc tccagcccttagcaaccaccattgtactttctgtttctataattttgactactttagatacctcatgt aagtggatgcgtgcagtatttgtccttttacgacttgcttattttatttagcaaaatggctacaagat 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cattggttgaagaggatatcctttcccagttgtgtattcttggcacccctattgaaggtgatgctagg tttatttctgggatctctattctgttccattggtctatatgtctgcctttatgacactatcgtgcgct cttgactgaggtagctttggtaattcattttgaaactagcaagtgtgatgcctccagtttattcttct tcctcaagactgttttggctatttggagtcgtttgtggtttcatatgaattttaggaaatttacctta tttctgtaaaaaatgcgattgggattatgataggaattacactgtatctgtagatggtttggatatat agacttttaaatgacacatcagatgtatttccatttatttttgtcatcttcaatttctttcaacaata tttcatagctttcagcacacacatcttttaccttcttggttgggtatttactaagttatttattcttt ttattgctattgtaaatgagattgttttctaaatttcctgtttttatgttgctagcgtatagaaacgc aactgttgaatgatgactttgtatcctgcaactttgctgaatttgtttattggttctaaccatgtctc tgtgtggcgtcactcttaagattttctacgtatcagatcatctaatttgcaaacagatataattttac atcttcctttccaaatttgatgtattttatttctctttcttatctaattgttctggctagtacttctg gtacgattttgaaaagaagtggcaaaagtgtgcattcttgtcttgtttctgatcttaagggaaaagat tttcagtcttttgccattaaatgtgatattcactgtgggtttttcatatacggtttttattatgttgc ggtaatttcgttctattcctagtttgttgtgtgtttttatcatgaaagtgttgaaacttgttaagcgc 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tggaaactaagtaaaaaaaaaaattatggaccttggtttaatagctagaggagcaagagtgtatcttt atgtgacttaacttctatgtgaaaagtgaaccttaagattaattattgggggaatttacttactcagg ttctatgcctagatggtctgcccaactaagaaaacttattttcctgttactccatcctatttttcata cttttatactgcacttgcagaaaagcatatatttctacccaatacgaaaattcctgggaacatatttt tctacatttcccaaattacttcaaaaagtaaacttaggttatttcatgatctccattacaatggacag gtggccttattgaatgttgtcctgtgaatacaaagatccagagtttaaagaacaaggtgtacttgcat ctcccacttagggtttgcttgtggtggagagagaatctagtttgcttaaaaggatgacagtgcagtgc cccaaaatatctgatatcattaaaagtctcatatttgtctttcgtaacttctctagggctgtcgatga caggagacccttaactcctatgccttgattatgtgaataagcacatgaaaatattttagttatcttag ttcacttttaaactaagtttcaattatcactagattctaaatatcatcattgagccgttcttaaggaa ctgattttctacatattcattcacttcacctatatctagtgtgtctactatttgccaagaaaaattta ctctcttaattcagcattccatatacttaacatcataaaaagtaggccatttttagttttctaaatta tttatttaaacatttctttaaaattacattctatcattacactatatttcaacactacagtaagcagc ctattttgtgatttttccttatataaaatacataattgaaattaaaaatgaagttaccaagagccatt 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taatttgtaaactttgtattttattattatgcttctcccacttggcataagcacaacacttcctaaaa gcataattttctatagacttaataactccctaaaaacctgttttggacccctatactatttgatatag gcagaaaaaaaacataatccatgctcaaatttgaaaaatgactggtcacatttggtataatactaaag gtaaataaaatcaagagtctatgaacatttccggacctgcacatttgttttattaaaatgcataattg tctttagtgtgtttctatttgtttatactctactgattttaattaaaaataccaaaatacgtttatta aaaaactgtcagaatctaagttgttaaatatacttaactaggaaagtaactgtttaaacgagataatt tatagagaaatgtggtgtattgccaattagatgtcaagatacaatacaactgataatgaaaaagtagc attttcttagggatggaatacagtgtaaggaacaccccagtaagaatacaaaaattactgaaaaaaaa tcttccttcctgaaaaaccaagtgcccttcaagtgcagaacctcatccaactaattgttaggtatcac taaagcctgataccttcaattttctggatcattcaagctgtatttttgagtccttatactagaggagg taaagagctataaaaacacttaatggtatctgatgtgaactgtggatcactttgacccatcacttcta cgtctacatcttggataaattcccattgttgtcatagattgtacaggtttaatggtgcgtttgtggag ggggctcgcttatagaaaatggagactctgaagggataaggaataaatgtatcacttcaggtctttta tttgaaattggggtccagagagcctttttgtatcagacttgtcaaaccatttccatttagtaattata 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gtttgctagactctttctaattatctgcaaagattttaggaatgttttaatgttttaatatttacaca cctgtgtatttcaagttcagtcaaacactattgttaaaactaaatcttctcatctctaataataagat gtgaacttatcttggaaggtggttattaggatgggagagataatgtatttcattcaaagtaaaaatat ttctctgtttctatctttctctttctctgtcatctatttatcatctatatccaggtatctatgcacct atgtagactagcattcaatgaaccatagatattattagtagtagaattgttactaatattaaaataag aagtatttaagaagaaacatgtcctaaagcataaggtcaattattactctcatgttttttggcatatg aagcctaaaaagtgtcaatttcaagagagtattaataaagattgtgataactgaaaggttcctgcttg aaattttgtgtggtcttacaaatatataaactctaagcatttcagtgagccaattactgactaggcac tatgtcttatgactcttttgtcatagtatgtaaaaaacaaagagtagagacatcataaaaattatagt agatgggcactagggaattacgcaaaataatttgtagatttaatgtgaaaccaaaacatctgttcaag tcaatttcccacaggtcatgtggcaaagagtatgagttccagactgaggagaggaaaaggttgttctt ccacagggaaataaactgagtgtaataaacataatttttcttcttaagcattatttaaaacaaaaaaa atgccattaaatctatctttcctgcctctcttatcaatgctcccttccctttcaccacttgtttcaaa ctccaagccttgggattttattttggctttttgccttaatgtaactaaaatgagagcatcacaaatat gaagctcatcaaataatttagcagcattttcccctgtttttaactttctctttggaaacgtagatttc gaaatttaagggcccaaaatatgaaatgcaattataataggccatttgttcattcagcttgataaact tgaataaatagtattgaacttttaatgcaaaaagaacaaaacaaaatagaactctccacgaagaaact tttcaatgtttgcatttctgtgtgaggagaagggtaatgaatgtgggaaccttaatggaatccatgtt cttccagtgatgacaagggtcaaaatggagaaaaatggtcactttctacccagtacattatattagtt ctatgtggacaactataacatagctgatgctggttttcaggccataaatgtaggtatgtattttccta ctatttataaggcaaaatttctatttgtttaatgatttctatataggtagattattctgtctttagga ttaaaaacgacctgtagaccaagagactttctaatgtccaccttagagtatatggcttttactgttac agtttccatttcctttgcttgcccctttgagagaaggaaaggagacatttgggatacatacatcaatg aggagctattaatgaataaatgaatgaaattgtcagtcaatttatccacatgatcatcaattgccaat aattttatcacctctgtgggattaagtagaggtaacagtttagaaatttgattttttgaaagcattta aaatgttcaaatatatcactctggtaactaagggaaagtgtattattttcttatgcttagtcttattt tggttttgcctttttaatttaaattgaacacttatatcaaagagcttgcaggattataatttgaattt ttgaagcaaagatcattttcttaacatcaaacaaagagtagatacaataggaataaaatcggcagaaa aacaagagtatcaaggacagacggggagggtgggtctgtgttagcatgtattgctatgaagaaatagc cgagactgggtaatgtatttttaaaaagagctttaatcgattcatgattctgcaggttgtacaggaag caggacaccagcatctactcagcttctggggaggcctccgggagcttttactcatagtggaagatgaa acaggagtaagcatgtcacatggccagagcagaagccagggggaggttgccacacatttaaaaaaaaa aaaaacaaaacagatcgctcaagaactcagctgctatcatgaggacagcatcaagctgtgagggatcc acctccgtgactcaaacatctcacaccaggccccaagtccaacacttggcattatatttcaacaagaa aaaaagtttaattggctgatggttctgcaggctgtacaggaagtgtggcacaggcatttgcttggctc ctggggaggcctcagggagtttttgctcatggcagaaggtgatgcccacacactttaaaaaaaaacca gatctcatgaaaactcactcactacactgaggacaatacaaaaccatgagggatctgtccccatgacc caaaaacctcccgccaggccccaccaccaacattgggaattatatttccacttgagatttgagtggcg gcaaatatccaaactatatcagggctcatgtccagttatatgtcaacatgcctgcattcgaaacatcc tgtccaaatcactgccttgtcataatacttatatttttctttattgaatacgaacacaagaagattaa ataatagcatttctactttaaaacagtgggcaccatattaacattggaataatagtagtaataacgat agtaataacaatgatataggctgggtgcggaggctcacgcctgtaatcccagcactttgggaggccaa ggcgggcggatcatgatgtcaggagatcgagaccatcctggctaacacagtgaaaccccgtctctact aaaaatacaaaaaaattagctgggcatggtggcaggcacctgtagtctcagctacttgggaggctgag gcaggagaatggcgtgaacctgggatgcagagcttgcagtgagccgagatcgtgccactgcactccaa cctgggcgacagagcgagacttcatctcaaaaaaaaaattaaataaataaataaataaataataacga taaaaggatatgtgtaggttttttttttaataggctgttaacattaataggcattgtgatttcaggga tatcatcaaacatcctggtcctaagacatcccctattgaataggaagggcttaagttaaacttctcat gagccacaattttctgattatatgtttggtgtgtgtaatagccacctcagtgatgatttgattagcct ggacccttacataatcattgaagtatacccatgttcctttatatacttctttagtgttgaaagctcaa aattaagcaaaatagtccccttgataatgtttagattcttaacatttgctttctaaagctggcaaata ctctcttcccagtgtcatgaagttaaataacatgttgcttagtgaggactttaatgttgccatgccat aggaagaccttattcgaaatccccttacctgggagaatgtcagattattaccccccaacttgtttaac acttttaggattttaaaggtgttcacatttgtattagaacaaaatactattgagaaacatttctagaa aaaaattatctttccaaattaaaatcagtggtatgtaatgtaggagtctgattataatgattaaaata catgggctttgggcatactgcctaggtgaaactcctggtttattgcatcactattagtataacctatg ggagttaacctacgtaagcctcagttaatttttctctcaaattgatctaataatcgtctctcataggc ttgttttgatagatatttcagtgtatataatatacttaggacagtgcctgatatcagtaagtctcctt ataaaatgcctttgtatttattcatgtcaaaggaaatatgcaagtattgcattcacttcctaggtgcc tttttgaattgagctttgcatggttagtttgtataaaaggttcagtgaactttctcataatgattttt tattgaacatatggaatccattaagtgttagcaaaagtcactatccactgagctgtgtccaggggctg acagttatgtctatctcttgcaaaaataaacacatacataaatgcactaagacgtatattacctgtcg tcatctcttagagcatttccatttttcttttaagttttttctttcaatgggttttttatctttgtgag tacatggtaggtgtatatgtcaacggggtacatgaggaaggtgtatatattgatggggtacaagagag gttttaacacaagcattcaatatgaaatagtcacatcatggagaatgggttatctatcccttcaagca tttgtgctttgtattacaaacattctaattatactctgttagttattttaaaatgtaccattaagtta ttactgactatagcaaccctattgtgctatgaaacagtagatcttattcttatttttctaacatctta gaacatttccacaaacactacctgcttgttaaatatacctattctaatcttcatataatcaattactt ttttcctctagaatgtactatgacacatccatggggaaaatgtagtaatctaattaagactatttcct ctcattttatatttaaaagaatgtgctctatcaatttatttacttgtacagccgtaggcaacctctaa aatatttaaagttcttaaaagtcagatatttcagttaatattgtgattatatagttgattttgatgaa catgttcatctaccagaaataaattatacacacacattgatatggttaggctttctgtccccactcaa atctcattttgaattataatccccgtgtgtcaagggagagaccaggtggaggcaattggatcttgagg gtggttttgcccatgctgttctcctgatagtgaatcatgagatcagatggttttataaagggctcttc ccccttccctcctcactcattctccttcttgccaccttgtaaaggaggtgccttgctttctactatgc cctttctactatgcccttcaccttctactatgattgtaagtttcctgaggtctccccagccatgctga actatgagtcaattaaatccctttcctttataaattacccagtctcaggcagttctttattgcacata tatgtgtgtgtatgtgtatgtgtgtgtgtgtgtatatgtatgtatatatgtatacatatgtgtgtata tgtatgtatatatgtatgtatatatgtatacatatgtgtgtatatgtatgtatatatgtatacatatg tgtgtgtgtatatatgtgtacatatatatatatatatatatatatatatatatatatatatgaacaga gagagagagagagagggaggaagggagagagggagggaagcatggagaaagagagagtaatagcctaa atagaaataaaactagctccaagtacaggttcgtcaacactctcctatcatacccccaccaaagttaa tgttaaccacttggagccctgttcttccttagttgtggagtactttagcaaaattttaaatctaatta tgcctaattcaacgacagtgctaatttgaaagtgttagaaactgaagacctataataataatgagagt tacaaaacataaatagtgagacaatgatgaatgtagtggatgcatgtacgagggctatcatttgacag tagagatgatgctcaaggacagacaatgagtctttcaatgtgtggagaatgtgctgctgttacagtga tgtacaggaaagaaacaaaaactgaggaagtatcagtaaacaaaacactcaaacatatgagtatacag ctagaataaaagcaacagtactagatgacaataagcccaatgttaactcagaaagcagaaggttttta agaatttggggaatactgtggctgatgatacttatgtctcaagccacagatgccatatgggctctgcg cccagttgaatcggcaccacctggcagtaagtgggcaggtccacgactgccaggacatcccttccaac acttgtggagatcaccaggaaggggggagagacctgccttgacagattttcaatgtgggcgaaacagg tctattttgagaaaagatgttcaatagaacatatgtcagcaaggaagaagagatgatgcttagttcta aagctccaaagagctggcttacactccaacttggggaaaatgcatccgggaaatgcaagattaatctc atcttagccattcttttgaatggatggacatgacccctttctacttgaagacagaaaacataaccata ttgatttcaggttttcttcattggtttccatttaggattgttcctccccatcttctttctgtgtaggc atcccagttcccaagtgttcatgaagcacgtatggccttcaggggatgtgtctgtatacattgttatc ttatggatgcacggttttgtctgcaccttggttctgaatgtctttactcttgagcatctgcccatggg tccccttctcaaggcctcaatttcttgagtttaacactgcatggcccatgcagcttttcagttaagca tctcttgctatgaccaactcttttcctcagtcaactcccacactcttttcagggacaggaaaaatgta gccacttgctggctgcactctgaggcctcaagaaatttagtgaatctgcctttgcccttcttgctgat gaaatactgccacatcaggccccctcttcggaaacctacaagcatctaattttcttgcttcctcccca actttctttttgactcccccccatccagagagttcttatgtctactgtactaggaaaaactcattctt aaggtatggttttcaaatcattctctggtctggactttagctacggttttaaatgaagaaacaaccca gagccaaaatataatgaaactatttccttcttccacagagtggaaactgctttggggttaaagggcca gtgaaccaaatagaaaaggatctcagggaacacagattgaagagagagaagaaaaaatatgaaggcat tgttggttctcttttgagtttaaaatctagtggggattgtaagcacacacacatatacacacacacgc ttacacacacacaccagtgaagttatgaaggattttgtcactccaacgaccttgaatttgattatcta ggtcagttgttaccaaagtggaatgtacatgcccaataatatgcgtgctaaacagttggggtagtgag aaaaaatactttttatttatcttgttctctagaaattaatattttgattgtatattttatagtgtatg tgatgtgtaagttgtgtctacaaaactagtgtcaatgtaatttaaaattacatatgtctgtgaatata tatttatatagggtacatgcttaaaatgtgtttacttctgaggtacatgaacatttttcccccaggca cagaaagacaaataccacatgatgtcacttaaatgtgcaatgtaagaaaagttgaattcatagagatg tagagtagaatcatggttaacagaggcttgggaggtggagtgagggaatagagagttactgttcaaag attacaaagtttcaactagacagagggaatacattttgagatctatttcaggaacattttgagaccct cactctaagtaataggaaatcattactttagttaacatatttgaatatgagttgtgatgttctatatc gtttatttggattctactaacccacacctagatttttatggcattacctttttactcactgtgaatat cctactcatagacagatgccctgggaacttggacttgaggcacccaagaactgagacagtgagatttg ggggcacaaggatctatggataagttcatcttagtgatgataaaatcaatttggcatgtttcacggac agtgtgcattttagaaagggtaaagacttggaaacgggatatttttgagcccaagtgtttccaataaa tagctgtataatttgaagcaaataattgattttttgttctctttgtgccctcgcctgtaaaatgggag aaatgtattcctttctcatccttctcatgaggccattgagagtatctaatgagatcagactgtgacat agcataataattctcatttcttgaaggcctattatacactttgcaagcactgtatgtgttgtttctac ttctcttgttcgtttttcctggaataaatatccccccctcctttacattggattgccattattcaccc tgtaaggaaggcttcatggttctcattttcatctgagaaaacttaggctcagagaagatcagtaactt atctaaaacacacacatacacacacagacatatctatgcccattattcttaacctagtttctctattc aggagttatctctgctgtctctgcttctgattataatctgtgtaagctgatccaagtgacacgattac agggaaattgtaagccctttgagagcagagactacctattgatatctacattttaaaatttgatttta gccaacctgtttatatgcaatgactaacaggttagtttgacttgcaataaatattccaaatcctagac taagtaaatttattaatgtaatgatttaacttgattttttcattggcatgtttccctgaagtcgtcat gcaaaattgaaaaaaaaaaaagtatagtgtgtgattctagattgaaattcaggaatcctccagggtta ccttgtttgctttccaaatagttcagattgcttagtctgaccaacaaggtccctgacacttggaactc tgtctatccctctaattgactttgtccctgatgacctcgcccagagatactcttcaccccagctatac tgtgttgctagagtttctctgatatcccatgctattgtttcctttgttctcttcataaggtaccattt cccacccgccaactcctgttttcctgatggacttttgtttcaccttacaagatcattgctaatgtatt tattttgagaataaaaagtgtaggaaaggtcacgggacaaagctgtacaccagacctttcccagacga acctagtgtataatctccctagtccaacatcatggcttaaggcagtcgatagatccgtcttaatgtcc cttttgagttttctactattattatatgaggatttatttttgtctgaattcctccctagatttgccct agagagcaatgactatttacagtttattcctctttgtatctcttatgttaaggccagaccttggcaca tattctagctgattagaagacgtttgttgaatgaccaagtgattgaacaaatgaccatgtgctctgcc acagtccggtcagttctactttggtttggttatgtgtttgccacattaaagttgtagcctgggaagtt cagttgtgagatgtctgcagaacatgaaaaattggaataatgaggttatttctaaaattgctataatt taaaataaatagtggtttattccatatatgaatatacactggaaacaaagaatttctagaatactgga gattcaatgataacatcattgaaattaaataaataataggattatgctagttactttctaatttacta gaaattgaccgtgtgcatggcacgtataatgagtatcatgggatagttacaaaaagtggtgcttagtg agtttctgtggaaaatctcggtaccaataaaacggaggatttccagaaatcgatattcctcaaagctt gacagtatttatgcacggttacactttgtgtgtctttcgtttgaatcaatggaaggaggctataactg aaaattattgttttagtgtattatatctttaataataagagttttaagaatctatcattagaaataat tattcctcaatttgtaattctcaacatttgaacaaataaatgctctgtgtctatcagttaatcttgcc catgaagatttaataaagcacgctagtttttacaaatgtgattttagagatggtcattacttggtaaa atattttgtgttaacacttccatgaatatgttctgtgggaatatactgcctccacattgcttgctcat gaagacatgatttttcacatcatcctatcagtattttgagaaagagattgatcccatattctatgagc atttgaacattctctagtatttttgtttaatcattaaaacaacccttgaagtctatgtgctacactgg ttatttccctcttgactttcctttacagataaccctctatcataaacaacctatctatatttgttgtc tccacatcatgttcccagccctgctttaacacactgcacattgacttctagcagcaaaggctcatggg aggtactctcatcaaggacactgatggtcctcatgttgctaaatttggtgggtcctctacagtcttta tcctagttcaccttattatggaccactgtcaactctgttctgcttaaaacactctgttccttgcttat atgactctacactcttaactcctttgtgaattcctcatctgcccttccattaagtattgacgacatcc ttcatagttttgatctaggacctcttttcctcttacttgacattatgtgggtaatcttgtctttgaac gcaattaccattcttatgttgatgacccttaagctataattccagcccaaatcatttttctgaggaag ctacaagaatacacaaatgtctaatagatctctatttagatgtccctcaggtgcttcaagcttaaaat actcacctgagctcatcacctcatctataaattctgcttctcctccctggctccctgatttatttaat atgaccaccatccacttagttgaataaagcagaagcctggacaccatctatacctccaattaatcact aagttttgttgttaaatacgttcttacattttctctctagaatgtcttattttccccatctttacacc caaaaccaaaagtcagatgaccctgatctcctgcttagatttcaaaacactatctcttgcctagactc tggaatttcagtcttgctcctctccaatctatttctacaccctagactctggaatttcagtcttgctc ctctccaatctatttctacacaaaagctagagtaattttttaaaaaacaaaaatctgaatgtgttcat tttctgcctaaaagccttcagtaattcttatttgttcttccagggatagagtaacaactttcagacct agtttattagctagttctttaaccacaaaggactctctcacttgtctactccccctaacacacttcgc cctaacctttgccattcctccctttcccttttccttcccagatggacttaagtcctttcagattctta aatgtttcttcctccagtctcttacatctcttttccttgtaactctaaaaactacttagcttacgcaa ggaaaaaggtctgtacaattcccggaatcagcgatcctaacgttccctgttgtttttttcgttgggac atgaattcattcacagtggctctaaacatcaccacccctgcctatctctcccattcctactttatctg agcttatccatactcttgaagacttacatattttttttctaccaggaaatcattactagccttattat cccactgtccaaaccaataagtctgattaggtatctgtatatatttaatattactatatgtgtttttc taacactctagtagaggagaaggtgtatttctttctgttttttagaagcctgtatttctgctattata gctcttaaggaactctcatgcaattgcctactagaatgtaagttacggtaggataagaactggatcag tcatatcacacatccacatataggacctagcaccatatctaacacacagcaggtactcaatacatttc tttcccaaataactaaagagtttaaacaaaccaaaatgattaaatgagaagtaactgttttggtaatt cttgtgtccttactagagtctaaattgagtgatttttatatcatcagtttatactcccctttcccaac cccaattctttcttttttaaattttttaaatcaaatatgccttaaaacttcaggatcagttgagtaaa atgatgcttttgtcgtcttttgcaaaataattgtatttcagaattttgatttagatattataaacaca cctaaaataatagctttagtcttaagatgaagtgcttcttaaactccctaagatgggttggactatgg atatgaacatggacaatatcacattaatttgtgtacacagttctaacacagggtctggcatataagaa caagtcagtaaatagttgttgaatggaattgaaaatttaagtagcaaataaagtattttgacctacaa agcaagaaatcacattttcttttttgtcacagttccttaggaagataattaattttttagtatttaag gatgttaaatatttattttatgttctatttactaggcttctttttatgaaaattaattggtgaaaata gcgtacatatcttcctttaccagaacatttacattttgggcagtaacgctggcttttgttaaaaaagc aaaatatgtgtgaaatttatgtttgagttgatttcaatgcattacatttccattttaaatcttctttg aaatactctatttttgacaccatgaaactgtattagatcttagtatgttagcaatgttttgcagtttt agagccataattattttaatgaccactttcagcatatacgttttctacaggaaaaataatctcaagaa catgaaaagtgaaatctatattttgggtttcaaaatgatacattttagctaaaatatcatagttttaa tttctcagtgaaaaatatagtgtggtaatttatgaagagactcagtgtttaaaaattatgactctata gtcaagtttatgtttataggacataggttattcaattacatttaaaataattaatttagaaaatgtga tcaatgtaacaaattttacctgttcttttctaaagctaaatttgttgtttgaagtgtttcttctaaaa tgctaatgaactatcaatttaattgttgagcttagagttagaaacttaattatattgccagaaataaa gaaacaaatggatcccaaaagattcacacattagaaatgtatgccagggaaatgcttttgaatgtgtt caagtcatggcttctaactcgtaacttataacttgtgttatgtctggcttcattcccttaagaaaaag gaataataatgccttcggagagcatcccagctgtaagagctatgcattggtgtctaaaaaagcttctc actcctcataccatcctggtctgggaatttaaaaaattgtcatcttttgataatctgtatcacatagt cttctgcatagtcatatgaggttagaactgccccataacttttgcagggcctatagtaagtgtgcaaa tggttgcctgcatgccacatatttaatatttataaggtataaagtcaacagactattaaatatatcct atctgctttccttgacaattatacaatcataatgatatggacatctagattcgatttagaattctctc tctctcattttctttttcttctttctttctttctctttctttctttccttcctttctttctttctttc ttctttctttctttctttctttctttctttctttctttctttctttctttctgtctgtctgtctgtct tgtttttttaaatagtgcaagcagtttattccctggcaaggaatttggaaaaaactcaaatagcaaac cacttgatacaataaaataaattccttagagttttgtactggaatgaggcagcttggttagagctaac cctaagcctgttatttaggatacattggcttttcttaagcttaaaaaaaattttactgtgttaatgac atttaacatgagatctatcatcttaataaatactacatgcacaatacattattattgactctaggtag aatgttggacagcagatctctagagctaattcatcctacttaactgaaatgtaatgtctgttgattag taacttcctatttcgccctatccccagcccctggcaaccaccagtccagtctttgattttatgagttt gactgttttagataccttatttcaagtaagtggaatcatgcagtatttgtctgtgtctgtcttgtttc acttagcgtaatcttaaggtccatccatattgtttcatattgcagaatttccttttataaaggctgaa tagtattccattgtgtatatataccacatttatctattcatctgccaatgggcatttaggttgtttct gcatcttagctattgtgaatctgttgccttttttccctacctcctttactccatcctgcactgtgagg aactctgtgcacatagatctggtcgccccatttcccacccacatgttcaagtttttcccactcacctc atgcaaagatttaccccttagccatacccagtaactgactttgaaacatttgcccagggagttgaggg attctgaatgccagatcatgggagcggggcttctagtgagcatgttggcttggtcctacagactccta atcagagctttgcctttgaaagcatggggcccaagggcaaggaccctacttgttaaggtctaaatttt ttttctgaaataaccacatcgagcttttatgtgtagatggcctaaattgggctaacccagaggcagtg acactcaagtagtttacatctaagcgctttccatgtgcttcttttcccatttctgttacttcttacaa aataaaaaatcagcatctcaattaccctgatttgatcattgagcaatctaaaaagtatcaaaatatca catgtagcccccatatacatacaactgttatatatcactataaataaatatatacacattatatttaa aaatcaatactttaattttacatgtttaacaaatcactagcatatacattccagattgaacttacgag ggatgtggaaaagattcagtgactaaataacaataaagtactctaaaaatgaaaatgtgaaatggaga cagtataaatctaaaatcatatcacttatgaagtattgtttcaaataaacaataaaatatatcttcaa tcaatttaattttattttagttgtataaaatctttcggtcagcattaacctaattggaacactaaata ggtacatctaaaaaatataatcccccccaaaaatatgtagctcataagagataatgcattgaacacag ataatattggcgttaaaaacagaactctaccacatttgcaacgaaatgtttatctgttcttcctacta gaaaataataaaatagttctgcatgagcttgaactcgaagtattaggtgtacaaagaccttttagtga atgaatgctagctgaaaagcaaattttaaatatgaaaaattagcaagacaaacatttgaatttgtggg agatgagtaaaactcctataaaaatgaattgtttagtgttaaacagattgtgtatgaaatattaatgg catattgtcctgagctccccttccgctgtttccatgtagatgactgaatttcaaacagaaatatgcca ggaatgattacgtgaatgaatattactacatgagattgcttaaagagtatttcttcttttgccttctt tttactttcgttatttcatttagtagttagaaaatactgtctacaaatatgtgagaactgcttaattt atttttgagacattaattaattcaactaaactatattgactgtgtgagagagattcccttggtgaata tgtggatttttgcggtggtaagaactctcctctggagcgcaaatggtattgctctaggaataaagcat atacctcaggcccagatgaaccagtgcaatctacagtaacaggttcaaagatgacctcatgacctact gtggactaataaaaatcaaggagacctactgcaaaggtttctgggaaattctttttctcttgcgttga actaagtaatatacatatgtgatagttagagctgcagcctttgtaataccatgacagaagataacctg aaataaggctgacagacacaagagggagacctaagagtactgagagatatggagcaggaccccctgat tgaacttcacttgcagcccccttctgcagttttcaatgacgtgaaccagtagaatccctttgtttact gtttttgattaatttgagtgcagctttatgttatgagcaactaatagcatcctcactgtcacaactgc cctctatacggcaggcactttgtgatactaaagaaagcagtatacagagtagagcccagtgaataaca gggcagatgttgcaattaaactgcctgtttaaattctagctcttccactagctaacttgtgactatct aagtaatttaaccttcctataatcatacctatcttgaagacttgttgtaagatttaaagcacaacagt gctactataaaacaggtatacagtaaagcttagctacttttttattaggccatatgatatcatttcat taaaatcttatagccatgctataaggtattatgatcctcaatttataaataagacagctcaagttttg gtcaagtgactttaccaaggtcatagagctagaaaataatgattccaagttacaagccaaacctcttc aatgccaaatttacatcatcccccattacttgaagtgtaagattcacatggacagaaatttttgactg tttgatcactgctatctccttatcatctaaaacagtctctggtccatattaggtgttcaataaatatt tgtagagtacataatttccttcacagactccacaatctggtgaaggaggcagacatgtaagagaatta tttcaggattccacagttgatgctgtaacagagctaaatataatgaatggaggaggaatgaataagtt tgtctgggagcaatgctatggctattgaaataagtcttgctcatgctttgattgaaatggtggatata gatcacacaacaaataacaattagataacagcttgttgggagaaagcgaggatcagtgtttgccataa acatttctcatagctaatgtcaggtgtttgatttctcaacattttatatctttgactttgattttctc tgtttttattttttaactccattctcaagaagtctgcacataagagtttcaacatctagcacttcata actccgtcatctcctctcaggcttagagcaaattctgagacgtggatttatcgtcgagtgatttcttc ctggcattttatctctgagaccaggatctggttgctaagcatgtagacatagaaatgcatttcttcat tgaaccccataggttcaaactagtggataatgagcacaatgtcaatgtgattatttgtaatgggggaa aggttaccggagaatattacacgaccatccacatagactaacattttcctcatgactaagtttactta gcaaaacaaattaaaaacagaagtttgtttagcagcacagaattgaaggaagacaaccagatggttat gaggaagattcatccaaactatgccagaactgaaagaaattaagttcattcagtacaagaattgtcta gaataagagaatccattttgtgtcagcacttcccaagttcttgttaatgctaccttaagttcaattca aaccaggcagcatttattacgtgttgtgctgggtcctaggaggaccgcgttttaagaacttactgtga tcttctagatcaagtttttatttcaatatttctacctcatttctgattcttaggtgttccttatttcc caatttatcccctgcagaaattgaggcaataagatgtctatcttattgcctatggtgttgattattta tgttatattctgttttgtgaagtttgacctctacctaattaaattacattttcaattgtatcttggat tgatttattcaataagtattctttaatatttttgcatgaggtcggtcaggtttcatcagacattagga attaattataaaaatctctagattggtacttggagcttaaaggaataaggtggtggaacgttaaatga ggaggaaagaaccagcagagctgggataaaattcatctctatcatcttcccacctgcttgatctctgg catataatttactatccgtgaacctcaggtttctcttcagaaaagctgcagggttgttgggggaaata aggcaattcctgggcttcagtatgttcaaaacagagcattaatattattatagacttttgatgattta cacaattttagctttttggcaagacatatttactagtactaagtaaaagcacgttgactttctaaaat gaaaatgtgtatgtgaggatgaagaaaaagaaagtgttttgtttgataatatagcattataacactgc acaaaaaaaaaatggtatatgcagagacttccatcacttgcttatgatgccgcattgggatctcatta ataagacacttcctcagacacttcctttgtgttcaataaatttcaatttcctcctttccttcagttca cttcaagaaggacggcagcaactttcttgttgccaaacctgacaaatgttttttagtgctgattatac tcgagcattctgtagcaaaatgctgtgggtgaaaatgccttccttcttaagggaatttagcttctgta gtaccagaatctccttgttgaatgaacatgtactgcctaagtcttagtaatccctcctttttgagccc attttctggcatctctccctttaatattcctcaaaaagttggatttttcctggacttttcatattaca gactttcctttggtcatcctcatccattccgtgattccaactacattttccctccatcctggcatctt ctttcttccagacttgtatatgcaactgcttccattcatacacttgaccaaccttttaatttctataa gatcaaaaactcagctcacaagctttcccctaccatcgagcggggttcttcttttgcttctttgtttc agacaatggcaccaccatactcgagtaaggcacgttcatttatcaggtcctaccaaatctacaataaa ctctcttgaatttatccacttgttttcatttgaacagtcatttctttacctgggtagcctgcaccttc tacctgcattgattcagcagtctcttcaccactggctctccctccctctcctgcctctcttcttgctc cttcaatttattctctactcttcatagtgacttttattaatgcaaatatgaccttataactcccttgc ttaaagacccactcatgtttgtctttgtatccataacttccggcctagggcttaacgcatagcaggtg ctcagtaaatctgtggtagatgaaagaacaagttgtataaatactgaatggtctgatgtgctctttgt tgtgtcaagaaggacattttgcagtcaggatagctacatcagtcctttagtaggcatttgacagcact cgcattattcctcaagagaagatggatgtattgattctgtatttcaaatgacataacttttgtgaaat aagaggctgccacggtaatctgagggatctctcaagttcaagggactccacagtgctttgtgtaaggt aacaggctaaagggttcagtcttaaactttcttaagactgtagttcagggttcctatggtggggctat aaccctgaattacatcctctttcatttcatgctgataatgagaactacaaaccaaggggtattaggaa agaatccaggtttgatgcagggaaaaataaaaacaactgataatctctagtgtccccaacttcaagaa ttcctttcttctttacaccaagctttttttctctgccaggacttactttgtcttctacatgtttaagg gagaaaaatgagttaacagaaggggaggtacagcatttctatttacttagatgctagagaacaggatg aaaggtatgaaaaatatgaaagtctctctctctctctctccccagccttcccccgcttctctctctct ctctctctctctgtgtgtgtgtgtgtgtgtgcacgtgcgtgtgtgtgtgtgtcataatactcaacctt tcttttctttcaagcatatgttgtggcagagacaagtgtacatcaaaattcgtggtccctctttcata gtatagagttcttgctaggatccagctgcaagccagcaactacatttcccagccccactggcatctag ttagagccatgtgactagttgtgaccaattgaatgtgagtgggagttatgttgcaggcataccttttc catcttcttacttcccatttgctaaccttatggaaaagagtcccaaagacctaggagatgaaaaagcc taaaatggaaggactcagagtccctgaattactgggtagagaaaagctgtttgcagatgggaatgccc attttgtagtattctttcttttcttaagccactaaaattgtgggatctctttgttatagctactggca ttaacctcttacgtatacatacagctatgtgctacaaagaggaatagatacattttttaatcgttgaa aggggagaaagaaacatatttaggaggaaaataatttagtctctacaattgaaaagtgttttatgaat aatattttgttttggcagcatattaaatctcaggcagctgaactacattaattttcaattctctatat atgtttttgtcttcagggtttagtaacactgatatataacagtttctttcttttaatttccaaattta aatgtctaagtttgccttctaggcagaaattaagtcccattgtggaatgagattggatcaacacttca ccaagatcattttagttctttgtaatcttaaatgaaataagctaataaagcattaaattagcatgttg taaaacttcgtgaagttttaatatgcttctaagtggcagctcttagcttattatctctaaagctaaag tcaaaataaatgtctcagttgatgaaatggagatgaggcaacattttatcaaatttaacaaaatattt tatatctgaattataaagtccagattatctagtaattatcatataaatgtatttaaccagacatgcat ttttctctaatcagtagccctggagtctttggaccacaaatgtgccttatctcaaatgctttaactgt gacattttgctttagactagctcgactacttctacagaaattatacacttcattcacattcatccaga tgaaaaaaatacatgtagaaatgatcataataagtaacatttgtttaggatttcagagtttacgaagg gtttttctattcactttctcacttgttcttcatgtaaactggtttggtggacaactgtcattatccct gttacctggagcccctgggtcttagggagacttcttgacttctcaaggtcatgaaggtgctaactctg accgtgtttttattcctactgtgccacacttctcaggtaaaaatcatattgcagacactttaagagaa gtacttaagaaaataaattcctccagagaattacatttaagttgtttcattaactgcagtgcataaag aaaggaaaagtgttcccaaacccatgtagtattttgctattgcttatggtaatattctgcacacctaa tattgtcagcataattttccatgtaacaaaatgtcctaaatcagcaatgtccaatataactttgtgtg atgataaaaatgttctgtctctgtgctgtccaatacaacagccactagatacacatgactactgagca atggtaatatggccagggacactaaggaactaaatttttatttaatattaaataacgtttaaatttca aaagccgcatgcggctagtggttgtcatcagatactgcagttatagaaaattagaatttacctcttta aatactaaacctatttttaatagtaggatttttaaattaaaatagttctaagtgcttttaagtgatac gaagtcaaatgcaagatttctgttttaatagtactctcaacccagagacaatcttcatgcatccttat acatgttctttgttgccttattctagttttattttaacattaaatgcctctgttctacttgatattga cttgcttcagagaacaccaagtatagtggaaagaaacacacacatgaggacttgaggctaccaaccag gttcaactaaatgcactctgatttaattgtagtattgggatcccctgttgcatttattgaagaagaaa aaaactttgcaaccaaaaagatatttgaaagcaactgttcttcttggacacatgatccctcataaagt ggggcttcctgcttttcagagacttaatttctgttcatattcatttcagcaatagtaataatgatgat ggcgatgatgataataatcatgatgatgcctaagtgttgtagtaatgcttcttctgagccagacgtta gtcaaattactttctctacattaattcaggcaatcatcacaacaatcccacaggacaggttttattat tatacttatttagctagcaaatgatataactaggttaagttacttgcccaaggtcatactgccaagac agtggctctagtgtccctgcttctgaccatatgttatgctgcctatcctagagcttttctcttctaaa atagtaaaataatatattctttgtttgtttcatacttttttttttttttttttttttgagagggagtt tcgctctttcgcccaggctggagtgaggtggcgcaatctcagctgactgtaacctctgcccccaccag gttcgagtgattcccctgcctcagcctccgaagtacctgggataataggtgcccaccaccatgcctgg ctaatttttgtgttttcagtagagacagggcttcaccatgttgaccaggctggtctcgagttcctcag ctctggcagtccgcccgccttggcctcccacagtgctgggattacatgcatgagccactacacccggc ccatacataaatattttaagcgaagtacacatgcatgatcatcatacttttaataatttcatttaact gtttccaaagaatgttagtatgaggttttctttttttctttttataatttcaacttttattttagatt cagcgggtacatgttccctggatatagtgcatgatgatgaggtttgctatatgaatgatcccaccacc caggtagcgagcatggtaaccactagttcttcaacccttgcctgttcccttcctccctccttcctctg tagtccccagtgtctattgttcctgtctttatgtccatgtgcactcaatgtttagctcccacttttaa gcgagaacatgcagtactcgttgtctgttcctgcgttaacgtgcttaggatagtggcctccaattgca tccatgttgttgcacaggccatgattttgttagtttttatggctgtgtagtattccatggtgtatacg cgccacattctttatcctgtccaccattaatgggcacctaggttgattgcatgtctttgccattgtga atagtgctgtgatgttatatgtactttttggtatattcaaagagaaatgctattttcctcttgacata tttatgtcaatttaacatatttatgtcccttttctttttaggagcaccattctcttcctttaacatta taaataaaatattttttgcttttctgtttttgtaagtgcagttttattgacagagtgagacatacacg tcgatattgtgactagctgcatgtcttctattatttagaggtctcactcaaatgtagattatcaaatt ctgttagtgaagagggtagaacagcagaactaatgctggtttccttctctagcattatttgatgataa actaagatgataataccccccaggtcttagatacctgcagtaggacaggcaccctacatttaatgctc ctaggaatccttcaaagtgatagcatagttattatacagtaattgagaaaactgatgttcataagtta gaaatttttccgaagttgcaaagaaagtgaatggaagaattataccaagttctggccgggcgcagtag ctcatgcctgtaatctcagcgcttcaggaggccgaggcgggcggatcatgaggtcaagagattgagac catcctggccaacatggtgagaccccgtctttactaaaaatagtaaaattagctgggcgtggtggcac gcacctgtaatctcagctactcgggaggctgaggtaggagaatcacttgaacccgggaggcggagttt gcagtgagccgagatcgtgccattgcactccagcctgggcgacaagagcaaaactccgtctcagaaga aaaaaaaaaaaaaaaaaagaggattataccgagttctctttgattccaagcccaaacaaatccttttt tgcaatatatgacattgtttccctgtttgcattccccattctgtgtatcacacatcctgtggcctgat caaaattcattttcagattctgaatttattttccattgaatctatataaactataaagacagaagata tatgtatgtgtgtatacccacgtttctcttccagtgtcaactgataaaaatagatttcaaagtctcaa taacctttaattccctttttctcttaaaaattctttagaacttgtacatgacattctgactctagcag attttagaaaacagagaggccattagatattcataccttactattcagatgaagtattcaatgctaaa ttatgtaatttatctgctttgcaaattgtatggtcagattgagttccacaaaggagagataattttta atataggcattctgtagcttccctaattattgaattagtttagagcaaaatccttaaattgtatcgtt gctatgctcaaattttgtatacttgtccacgtaggctatattaagatttcattgaattttggtttctt tctcagtgataattcaatatatcaactcaccactcagatttgcctttgggaaaatccaggcccctttt ctggatttttagagcagattttaaaaaagtgattctgtatatgtgttgaaattaaccacatctcattg cttttgaatgattgaggtaatgtatacctactactttaaaaaaaatgacttacttagaaggtgtccat agttttataagttccattgaactggtttatattgtatttagaaaggaaaactactccttttatcctta agggtgaaaacctggattttattatacaattaacacatatttattttttattatgaaatatatcacaa tataaacgtttacagggagtgtttaaagtggtgttgtccaatggaaatataatgtgagtcaaatacgt agttttcaattttctactagccatattagaaaaagaaacagagaaattaatgtaataggatactttat ttagcctagtatatccaaatcacaattatttaaatatgtaatcaatataaaaattactaattatgtat ttaacctttttctttagtaagtctctgaaatctagtgtatattttacatttatggcacattgcaattt gcattagtcacatttgaattgttcaatagccacaggtggctaatggctaccgtgttggacagcacagg tttaaagaataatatgaacatctgtgttccaacattctgagtttcaaataagaagaacaccatcagta ttttgggagaagctccctatgttaccccttgctaatcaccttccttccccccagagccaaaagtaacc attatcttgaatttctagtaaacaatgctcattttttaaaaaacgtatgttcaacacctgtatttgta tctttaaagagtagctagttttagtttgcctggatttgaactttatattaagggaaccaccccatctc taatcttctctgtgaattcttttctctcaatactatgttttacatatttacgttcatcaatgtgcaac tcattgtatgtatataacacaatgtatatattttacatgcgtatggacatttgggttgtttttatgtt tttgttcatcacaaaccacaacacacatgtgttcttgtatatgttttatagtgcatgtttaaaaattt ctcaacagtattcgctagtagtattgtcaggtcatagggtatgcacacataaatagaaatgattgatt agctgcaatttgtagtgcacacatatttgctatgtaagtgatccatgtttaagactttaactgaattt aaaaaatattttattggagccaatctaaatgagctaagggtttgtattgtttacataagcaaagatta cacttactgggtcaattcggttgattaactttggatatataaaatatatagctagttgttaaatagat ataattattaattggcattacttttgtttgtatataaaaatttcaaaatatccatgacttaagcaagg taaacacccactgggtggcttaagcaacagaaatgtatttcttgcagttccggaagttgaacgtctaa gattaaggtgatgacagggttggtttctggtgagtcctcccccattggcttgcagatagccgccttct ccttcatgacctttcctctgtgtatgtgcatcccttgtagctgttcttccttttatgaggacattaga cttattggattaaggtcctacccatatgaactcatttaaccttaattacccctttaaaggccctacct ccacttgcaggggttaaaacttcaacatatgaatggggttgaggagacctacttcagtccataacagt ttctatattctgaagatggtctttaattaactaaacagttaatgttactttactgggaatgtcttttg gatgggggaataagctgatgatatgagaagggttggtgaatttctcataagtgtgaaatttgttgggc cggcccagcatgattttcaatcaaatacgctttggggacaagtaggttgaatcactacgagaggttta aaagaaagcaagttgtaattgcaacttttaattgaaagaaagacaggctttgttgatgtgccagcaag actgataactggctttaacgtagatagtaaggcagcagattcaatccactgatcgtgatctactagtg aatttcaaagccttatgcaatagaactacaaaccctttccttgcccaccttgcaggtggatccatagg caaaatgaacatttgcaaaaaagccgctatgtttcagaatttgtgctagggctttaatatctataatt tctccaaatcctcacaatttaagaattaattcaacttagccccatgaatagggtgaaaattctgagat ttaacaaactaaaataagttatctgaagacagacaaatagaaagagttgagatattctatttgaatgt aaaattttcaaaaagtagaatgacagcgtcaggaattacagtctcagtgttgaacacaagacttagga acaaatttgctgcatgtaatttcattgagatgggacaaagtacagcatacgtaaggaagttttagaac aaataagataattattttacgagctttgaaacatgtgtaagaaagatacgaataaaagtataatcaca tttgactaaaacatgaataccttaaaactgaaaagcactgagattatcattatataattttgaatatt ttaaaccacaatgctttgggagtgcactgtaatattttagaattggaattttaacttactggcttaaa aagtaatgtactttgttttaaattcaaagattatcttgtaaattcagttcgatctattgaaaaaatta taaaattcggcaagaagccaaagaagaacaattatgtagctcaagataattaaattttcatgtttggc tttagaaatatattcgtcgtgacatagtacatggtaatctagtgagcccagacaagtagttttctctt tttgtcaaagggaacaatttgatgcgtgttcaagttgcttaaataaaattttgtatgtgctttctcat cacaagagaacaatatgatttttgaaattatttttactttataaaagaaaaaaaaaagccctcacaga gaaaaaagaaaaaaatgatgatgtctttgaaaaacaaagttaatacagctttacatatatttgaccta catcagggttaatatttttcaaggtgaaacattagatgctggaacttgcaaaaacaggcaatcctcct ttagatgaaacggacactctaagggttaattcattcactgagacctattgtgaagtaagccctacaga gactgaaaaagttaaatgcaactcacaaaagttgctagaagagtcatgatgttaaaataaaataagta cacaatgtatgctgcaagtatacttagagccatgctaggtgcggttgagaagttcaatacaggtccaa gataatagctgcttctcctatagaacatgtcttctcattggagggataagacctgtgtctatgaaaca ggcgtaattacatagctctggaactatatatgccgaaataaatgagacagtaagtgttattgtactat aaagaatgaagaaatcatgatgagaagtaacagttaatgaatgttttctagaaagagtaggatctgaa ttggccttaggttgtaagcagagtttatagatagagtagtggtatgtcagagtcactctgggtgctta aacatacaaatccccaagtctcacccaaatgtgtcttcagatgaaaggaaaaaacaaatgacttgagc tcccccgcaaagaacacgggtggtatattgagcagccaaggagtgaccagagtggcaggcccatgttg agggacaaaagaggacaattagaatatgattaatacaaatttacagtgggatgagttgttagcctgag gagcttgaatgtgaacctctgtgcaaaaaggagtcattaaatacttttgaaaaaggtgggatgggaag aaaatgacattctcaagacaattagatcgaacagtattaagcatgctgacttattaagttatgcacct tgagagggtggaatgagggaaaagggtctttatctggagtaagacaggaagaagctaagctgtaattc ttactggactgtaaattatgtgcagatatattatctgtcatgttcgtgggcgcattctcagtacatag cacttgaaacaggtactcgataaattgtcaaatggatgcatggagtgatttccatgcaaaatctaata ttgtatagtattagaagggggaaaaaagcatggcattatgctagcagaaatgtcatttggtattgagg atgaaacattttcaacagtttgcaaagccatccactcaaacattctgtcactttccaataattttgaa ggatgttctttctactictaccttattacacaatgagttgagtaagataaagaagtcatgtgcaacaa aacagagggagattttctgaaaggcactacaccaggaagttgttgtactcttgcttcatcttgccatc ttggatatacttctggcgctacctccaggccagttcctcgttacatatgtcatttacttcccacatgc tagactcaccgagttaatcattttgctgcagttaacacattttagcagagtgtaggtttatgggtgag aaggaaatcaatgatgtttcaatacagggttcttttcccatcccccttatttccacttagaactgtct ctcaagtcttaatttgcctctaaacttttttcccagcttacattcttttctgaaaaatgcaacgacga tgccaatgtttgttgacctgaaatacattgtaaaacattcataatactttgagcagagcttccaaact cccatttgcctcttttatctcccttaccttggcccctttttgaaggcaatgtgatatttaatccgttt ctattgatgcttcaaaattattgaaaaactggtaattgtatttttccctttacttatcagttgctagt tgacaatgagtgtttgcccaaacaataaccaatcaaaaggtaaaaaggagattccagacatatctgag aagaaattctttggaagaagcccgtaaatggaatgggaattcaaacaaagccgtttccaaaagaaata ctaaatggtctctaaatgcaaaaggattgctccccaagcattttatgggagcataaaaagctcccaac acattttatgacaatacttctactcaatgacttcttgtgttgacatatttgttgcactcgacgttagt atttacagcttcttatcccaaatatttacttaactgaagccctgatgtttttaaaaacttttcatctg tgtttaacagcccattttacagaaacttatttgtttcatcaggcagatatttactgagaacttgcaag tgccatatattctaaaaatgctgatgataaaactgtgaacacaatagattctcatggtgcttatggtc agggctagcacacacacttgtgaaatgatcactgatgatcaaaggcataaacactacatttggaagaa ataccgagggatccagaagtatcttggaaacactagcaagtatagcagatggtgggattggtgcttca aagaacttcttgtggaagatgttacgtatgtaccttctctgtgccaggcactgctaggaagtgctgga gagaaaaagatgtgctagataccgcctctgtcctatgtgcttgtgctttgtggggaggtgagtaggat aatcccagttctcatgcagtgtaatgagtaccatgacggaaatgcactccaagaactaggcagcatga ccagagataggacatttgagaaagacttcactcgggtggtactatcttagtctgggtgctaaaataga tgtgatagatgagtaagggtgacccggaagcaggagggaaagggaggggctttcagaacaacaagtgc gaggacattaaggtgaaatagagtataatagtattcccagatccttgggattgttctccattaggcta aaacaaaggtgttttctcttctttaagatttcatgactgcagattgcataacagaaggtcatttaata gacctctaaactgaaggaattcttgaattaaatcacaacatatcttccatggccagagaaaccattgc ctccttatgtcgacattactaacagcaccagcacctgctgctcaggccagcgggagggttgggtgttg ctgcctaggtaatgctcaccaactgatgtcctgccatgagtagttttgccaagttccacaaaaaaaac ttagtgttctatcagcatctaatgagaattacagtcattagttaaataaaagaactattagataagga gcagaatgaacaacacacaatccatcagcttggtgaatggtatcagatggtttctgggtgctgggcag ctgtgcatccaagtagacagggagaatatatatgtcctttgccttatgtacttgtttctctaatccaa aggcacagcaatccgtggaagctgctatgataaggtgtttagtggtgaaaatgtcttgaaagccagta gattattaaagtgatgtttttaaaaatgcagatggagagtaagtactttttatctagagtagtagttc tcaaagggaggtcccgggatcagcagcgttagcatcacttgggaacttagacctgcatgggccccatt ccagatctcacttgaaaactctagggggtgtagcccggcagtctttgttgtgaccagctctccagggg gttctgacactccaaatgttcaagtttcagaacgctactcacaggccatcatgctcggcatcacctga aagcttgttagaactagaaagtcttggccccaccccaagcctactaaatcagagtttttgggagtagg gccaagaaaactgtgggttaacaaggtctccaagtgattcttattcatgtcaaaatttgaaaagcgtc gatcgaactgttggttctcagctttgattgcgtatctgaatcacctggggagacagttgagctattcc gggcccagatcacatctagaccaattgaatcagaatctatggaggcaggacccagacatcagtatttt aaaatatttcttgaatgatcccagagtgtagctaaggttgagaaacactgttctaggattaaaggatt aatgtgtttgagagtatgttaagatcttaggcaaatcacaagggtgttaagaactaccatcttcgcaa aaggagaatgtgcctcagatattctggtactgctttgattttaccttcagtagtcttacctattttga gtatgcttagtagtactaatatgaggcttattactaatatgttaaaatttgtcttttaattaagtggg tctaaacgttttaatctttaatctctgacccaactagaacttttctaaacattttcataatagtctcc accttgtcttctgaccttcacttatgttctttcagggttcttcgtgtgttactagtaatagtaatggc aagtgtttattgaacacttactatgtgaagattctaactggcttttaataatcacatcagctctggga ggtagaaggtagggatcctccttgcttatcaggtgagaaaactgtactatagagaagttagcaacttt tcccaggtcataatatgtgacagctaaagggagcataatggttggaataaaataaatctactctagtt gtaccgaaggctcatatttgtctcacgtacttgatttggtcgaggcccaaggggtcaatttccaatgc ttggattcctggatatgtagagttgtattaaaaatgctaaaaacctattatgtatcatacaatcatac atatcacctaaagtattatggaaatgaatctgtattattaagggaaaaaggcctgtgtgaagaacaac tgaaacttcattttaattgaaattaaataacatgcatcatacactaaaagtgcacgttatgaccccat gaattacttcaggtggctttgattcatgttacatacactaacaaatatagaagagtgatataatgctt cttaattaactactaatggaagtttactatttaactgcttcttatgtaagaatgtaaatgttttctga aatatcagaacttttcattaggaagcacttttaaaaatagcaaaactgatatgcactatgatttccat atacattaaattgaacttgtaaatgatgttataaattatagaaaccaaggggatgttcaaattagata tttgtctaaataaatcatgtatggattgaacaaatactcattgagaaataaatgtattccttttcttt caattatctaggattccttgtttatctcttcagaagcaaaatgtcttctgtccgttttatttccagtt aaacattcttcagattatgtaaataagttaacttccaatcctcttatttctgtttatctcaccactct tctaatttagacgtgatcaatatcttatctttttgcatttcatagacatcaggatccagaataattga gtgagctcaaaacaacaatggcaagaatgatgttttcagaaaactcagcaatcattcgtttaataaat attcattgcctaccaactataagcaaagtattggctaggccatgtggggtatacaaaaatgtattaaa tatggctcattctccctaagaacttacacctattagacaaagtacatgcataaaaattataatgtata atagaaaataaatacaagccctagaatgcacagttgaagtacgatttgcatttattataaaaagaaag atgaattggctgggcacggtggctcacgcctgtaatcccagcactttgggaggccaaggtgggcagat cacgaggtcaggagttcgagaccatcctggccaacatggtgaaactctatctctactaaatatacaaa aattagccgggtttggtggtatgcacctgtaatcccagctacttagcaggctgaggcaggagaattgt ttgaacctgggaggtggaggttgcagtgagccaagatctggccattgcactccagcctgggcaacagc aagattccatctcaaaaaaaaaaaaaggaaagaaaagaaaagattaatttcctgttagctaaatcaag gaaggcttcatggagaaaaaaatatttcaacacacacttgacgtagcagtgggatcaggctgatgtta gggaagaatgaatgacattctacactgagaaagagatattcagtatatatatgaagagcagtagagaa actaacaagtggaaatagactcaatttacaatacttgcctgcctggagtactctatacgttgactgta agttgcagtttactcagaacaatcccactttctacttgtttatcctatgtaatcatttattgggcctc cttttgctctcaaaaatatccttgtttggataatagattatcactctgttcctaaatgaactgccctg tgtcctatcccagtaaaagggtgcattcgggcccttcgtaactgcctccactacatggttgattgaaa ccagagcttggcattaagaagttagctgaacaatcagatttctattcttggaaaacccaagaatttca gaatagatacagaagctgtatagctttaataacatgacagagttgtagccttgaaagctatgtacaat tcagaattatgagggagaagaaattgaagaaacagtagcagccgggtaaatgcagaaacaaatgaggg agacacctagggggtgactgaggcacaataatggaagagaagtgcagtgaaattgcttgaactcttac tgatgagatttctactgttgccttgaatccaggaccacctatatgttcattctttgtcatgctcagag ttatgacagatgctgttattgaattccccagagactcccttatcgtctcacctcaaaccttacaataa tcccttctatctttctatccatccaagctggcttaagtaaagtctatgatccatattcctagtaaaca gagaagggaaagagactgaaggcaaaggccccaattagtaggctattgcaatatttcagggaaaaggc aatggccatcacattgttgtcccaggaatgagaatagaaatgaaagaagataatgaaagttgaaagga ctgggggggcttgacaactgtttagacttgaggagtcagataaaataggaagccaaagataattcaga atattttgattttgattttcatcaccaaataagatagtagtactatgaagaaaaaatggttaaaaaac aataataataaagagaactcctccaaatagtaccaagggagggagtttaatagaggaaattaattccg taggtgatgagagtcctgagaagccaaacgagaaaagatcaaaacaacccagggattggcagtcgcag gaagctgttctcacttatggctggggctttaagcacaaggtgacatgagatttcagaatttgaagtcg tctggaggcagctaggatcaggtggggcctgtcctgttcggcaggacctgcaaccacaggaggaggat gcgtcaagcagaaagttggaacacaagaggggattcagccataagccacaaaataccttccagagcag agagaaggagaaataccctgaattccgtattttccctgccatttagttccctgctattgccacacatt gacgtattccatccagagaagtccattggcatatgagtctgggaaatgtagttcccagggggacatga tcttaagggaaatagacaatgactggtgcaacaactgacctgtgtgaggcaggagggaaaaaacagga ataatatagtttttctctagatcccttcatgcacaaagatgcaaaagaaatgtgttggcttaatgagc cattctgggtggccctgtaggtggctgtcctacgaataagatttttagacaaaacagagatgacttca aatgtcacaagaaaagtatcagacaggaattaatattgacttgatctgtcacaggcgtcaatgatttg cattaagccaacgatcttcattgttaatgtctgggaaattgccagcagcattacgactacttgtgtgg attagtgtaacggattcccccactaacattcaggaaatcatgtcaagcacagagtgcctatgtaagag tggttgtgtctattcactacatttcttggactaataacacacttagccttcctgaattgccaacatgt acaaaaccagattggggttttttagttgttcatggaactatcatttattgggtagctcctgtagaagc aagatacagaaactctaattaggaataagacagtccctgtacttcaaagagctctcaggggaggcaca caagtaaacaagcaattattatcatacgttaggataataccgtcatggtgataaccactgagtgatag ccaaacacatggaagaggtacccaagtctaacttggggtagtcagagactgctttcaaggatatccga gtaagtgttagctaagacatgatacgtatttctaggagggaaattttcaaggcaaggtggagattgtg cagtgacgcccagagcctggattattttggtgactgctagtatttcagaatgacttcagcaaaagttg tagagaagatagaagacaacaaagtataagcagaggccagataatgaggacctggaacagtggtttgc tggtaaatgtttaacaagaggctcttggcggggagagagagtgtctgatttgcagcatttggcaaatt ttgttgcacaaatgctccagcatagccaatttcaagctaccagtgtgacgtcattgaatgcagaattg gaaagaaacgggcagtagcacagcattgtatagttattttcattacccagatataatagataaaatat ccagatggtatttaatagatatggatgcaaaatttaaatatatgtacattcatgtgcttcatgttact gaatgcgcacaacattcattatccattcattcacgtgttaatttaacaaacatttctgagcctctgct ctgtgccaaacgcagttctagctgctggaattacagcactgaaaaaaaaaatttgtcctcactgaggt aagacaaacattattatgcccattttacagctgagaaattaagacatatgaggattaagcagtatagt taaaatcacacaattggtacatgaaggaatcaaagaggaaatcagctctcagattttaaatccaggga ctcgtttctgctataccatactacctacctagttgagctggattttatcatggtttccctatttttat caccatgtggttggataagtaaaataaatatatgtgacctttcaaataaatttgggtcatttttcttg gaagctcatctggtgtgaactttaaaatactgcaattaataatgattataataccctggaactctgta gcaacctcttttgaagaactccaaggagcctctaaatgtatcaaactaagttcttcaagtgaattagt tatcatctgagagtaatatagacttttaaaaatgcattaattgtattaaccctttcaggcccatagac ttaagtgtttctttctccaaataaaaatagtaatctctgtccattttctttagagaataatgaagtaa ttttcattgaatatgtagtcaacataattacttcaattcaatcgtgaaggattttaaaaattatttat gtctactaacttaaagacatgcatagatttcaagaacttaaaaatgcatattgcctctttgccctatg cctcataaaacaaaattatgataacgttgtgtgttacagaaaaacgcactgattgtaatgaagggtgc ttcaaaggccatgaacttggaaagcaacttatttacagagacccccagcaatagcagctaaaagattg actgactccctttattttcagttatccttcagacacttttgacctcttcctgtgcctttctagtcatg tgcaatcttgtggatatctcttccttcctcttgttattttctatttcctctgtttctatttgtttcta aaaataatcatgtttgaatataggattagcttccttcccatctccccattaccaatctctcactatac cgctatgttattaatcttcctgagaaatatatcaggttcattacattagttaccagctcaaaacgtat cagtggctttctagtcctcacaggctcaagttaatctgcatattctgactttcatattctgggttcat gcaaacttttcaactttccctcttatacctacttaggaggaccctcaggttccatcatgctcatgttt caagccagaagttctcctgcctcttcctctatgtagactccacatagactatgatatcctgcttctct tttaatcctccatcttcagctcacagccacactcctctgtgaacagttaaatgattctcccacctctt acctcctatagcacttatttttcatgcagcatttttgagacttaattaaatctacagttttaaaaaat gtttttctaccacagtctcttattcatactaaaactttcaagtctatccattttgcttatacaaccac accgttaggtcttttaggtccaagaatacaagagaatggcaaagcacgttgtttacatccacacatac tgtgtaaattcaggtaattttttttaatcctatgatcctcaattacctcacctgtaaaataggtacta ctcatactgcagaactcttgttggaattaaataaatgagtgtattaaaaatgctcaacaagatttggc acaaaatcggtactcagtaaatgctaatcattattccctttctcttcaaagctccacaattctgtatt catatcaccctctttatatcatttgcaaaaatgtatcctattccaactctttccacctagcctcaaca tttacaaacactcctggtgggaagggaaagcttttgaggagagcacatctatactcatttacttctca gggatgcaagctgccctgcttactgagggcatatcttcatagtcacaccggagcccactgtcccctta tactctcaaatgggcagtagcaaatcatcttgatcggtagtaatgacctgtctctaaattttcacatg catcagataatttcttttttagtaagtgttatcttacatatatgccaaaatatcaccattatatggaa cactagctgaaagaaaaattattcagtagtcttaattttctagctaacataaattctctccattttca tcatccatttagattaaagactttactgttagctgaatattcagagactttattctgatttttaaaat ttatgaggttcataatgttaagacttcaagggtgagctgtttgtgtcatttataatgcgtgactagac agtaactagaaaatggattgttgactttacaagatttctccccaccacgtccccccaaacctgtgctg ctgtgtatttggcctgaaatctttacttctagtcaatctttggacctaaagcctaccagcttttagca tcctttaagattgacgtgtctctgggagaccaatagatgctaaaccaaatttcgtatgcacttggcaa tataggataataacaaccatactccctgcaattgtttcctaacacagatgtaacaaattaccacaagc tgggtggcttaatagacatttattctctcacaaatctggaagctaggtgtccaaaatcaaggtcaatt atccctctgaaggctctggggaagaattcttccttgcctcttccagcttctggtagccccaggtgttc cttgatttcaagcagcacaagttcaacatctgctcctgacctcacataaccctcttctttgtgtgtct ttctgtgtccactcttttctttattattattattattattattattattattattatactttaagttt tagggtacatgtgcacaatgtgcaggttagttacatatgtatgcatgtgccatgctggtgtgctgcac ccattagctcatcatttagcattaggtatatctcctaatgctatccctccccccctccccccacccca caacagtccccagagtgtgatgttcccattcctgtgtccatgtgttctcattgttcaattcccacctg tgagtgagagtatgcagtgtttggttttttgttcttgcgatagtttactgagaatgatgatttccaat ttcatccatgtctctacaaagaacatgaactcatcatttttttatggctgcatagtattccatggtgt atatgtgccacattttcttaatccagtctatcattgttggacatttgggttggttccaagtctttgct attgtgaatagtgccgcaaaaggacaccagtctttggatttagagcccaccctaaattcatggtgatg tcattttgaaattcttaactaattacatcttcaaagaccctatttccaaatctggtgacattcaaggt ttcagggacatgtgactattcaggggaaactattcatcccaccacatcccccttgaaaattctggaaa atgtagtaataaaggcttctgataaattagtgtggaaagtattcacggttataaattactaaaaagtc tcactgtgagctcttaatcaaaaggccctataaaacatttatttgcttgattaaaactacacatccga tattttggttttggatttattattatttttagacttggaataactattttatgtgaaatagattccat aactgaagcagcatacctctcaatttcccaacatttattttattattttttgtcttcacactacttaa taactgaggaaaaatcatttagaccaaagttcaccttggttgacaccatccagacagctacaggaaat aacaatggaaactaaatctctaagaaaaagagtctttcatgtgaaatattgcagagttgattctagat atatagctgttggaagaatggatactattacatagatatggcagagtggtatccagcacctttcaaca aagatctttcagagtcagtcttattatgtctggagaatttacccagggcttaggtgcttttactgaca atctaaccacctgcaccccacccaccgtctaaagctaaagtttattggaagacttaggaaatcagtct tcggaatgtttctgagactggtacacccaccacttcattaaagtgcttcacttcacttcattagacaa gaagtaaaatacttgtcaggaaattatttatagtaccatgtatatgggtatcttatttaatactactt aatgatggtactacaagttatataaaatggagaaataagtcatcaagtttgacaataatgatatttga tattatcattatcttttttattcgttcccacagaagtactctgttattggtttagaaaaatgatattt gatataataaagaaggaaaaggtggtaatattctttattttttgtatctttataccccagctctttca ccaatctcccccatctctgtagttctcctctggtgtccccaggcagtgaactattcccagtggttagg gaacatctcattgagtaagttacatcaacatttcttcacatttcaggacaacaggaacagtgccaaat cctagcccattgttcaactctcaagccttattatcctaataacacatccatcccaagaaagaattcat caagatcagagaggaatacgtataattttttatagtacagtatttaaaatgaaacagcttttggcccg cgtggtctcagtgggctcaagggggaaattcaggatgctagctcatctcacaccaagtttaataaagg gtgtcctataaaaagctaatttcttgctggtaaattgctttttaagtaatccttgctgttgcaagaga cccattcatagcgctgacactgggagccatgttggaaaggctagatatgctctgggagataaggtaag atccaggtggaatcttctctttacagaatgacaatgtatatagctaatattgtcctttgaggctagtt tgcatgcagttgctggtatggcactgctcagcagcctgctgcagataagaatgagtgatgatgcccta gattttaatggaacttttagagtgcatgcagcagtggggtgcagtcttcagcaaagaaaaacgagctg acttgcaggcatgagagatcatcaagaaagataaagaaataggacatccactctaggttaggcaaggc tttttagaggatattatggaaatgagcaagaaccaatttaatttttataatgccactccatttaactt taaaatacaaggtcaaggtactgtgtttttcataatgattaaagatttggagcactctttctgttgaa acatactgcatctgtttggcagaaaaaaaaagtgacaaagaataaaactgggatcagagaacaacaaa aacatattctgtcacttgcctaacacaagttaaaaagcaaaggaaaaagagacaactctgatggacat gttcatccttatcccaacagaaggatttatttacctaaggtcctattatttcaagttactttgatccc aggatggtaacataaaatgtacattttaaaataaaatggaagtataagatcaataaaaaccacatatc tgtggataaaacagcagattcaatcttgtggctgaaagtttgctttaacccaacatttggtaaactat tcactctgtaatttattaaaagacatactgttattataaaactatctcagtttgcatcttgttggttc tgtcaaaatttcatcctgctaattctcaacttgtaatatctctgatatacatgattaatctattttag gaataaaacaaaaactacctttatcttacgcatttctaggaagtgtttttagatgtaaagtaggggta attgtagtatagtggaaaggattttgaacttgaagccagaacatatgtctctgccaaaaactaggtgt gtgaccttaaataagttacttagcttcctgaatcttagtttgtttagcttttttctataaagtggcac acctatccacatcacagttttgttgtcaaaattaaataaaatactatattagaaagaaacttttagaa agaaatttataaactgaaatgtactatacaagtttaaatcattctcattattttcttaccctaaaatt ttgaccttatttttcttagcaaatggctgaatctgtaaaatttaacccccacgcagcatctggattca agagaactacggtcatttctttatacagaatactaattatacacatatagcaaaacacaagttttttc caactactctgtgtttttaaagattcagtgtgggcagaaggaattttatcaactatgttaggggaaaa aagtctgaagaaatgaaaataatgagaaaaagcactgttgatttaagtgcaggaacataaaacttcaa ggcaaatgtgaggccaactgagttcatatatatcctcacaaaatgatttagttaatttaaaaactttt ctaataagcaacacaggtaatcccaaattctatcttttatagctctaagagtccccataatttattca gcaattatttaccacccacttattataagaaaagccctgggataagtcttgagaagaaactaacaaaa acaaaacttgattgtttgctctcaaaaagctgggtctaaaataggcaaggtaagattttgttttgagg agcccgtattttccagcactgtccattgtaacattaaaatagtttgccaaaatcctcactctgtgggt gtatttgcctagggtgctaaaattgcttaaaaactttgttatttggctaactaaaatcactgaatagt aaacagtagcattagagatggcagagacattaggtgtcatgcagttcaactgcttcacctagcagaca aagacattaagttccatttcttaaatttaactatctggttgaggatacacagtagcagagctaaatca agaacctcttggggttagagtttttgtttatgcattactttgttttggaattaaaaacagtgcctgtt tgctaagttaaattgaaaatatgctctgaaggagaaaaacagctataaaaatagacttaacttccaaa ctatggatcacaataaactaaagaaataatttctgtagcaataaactccaacactttccataggacca gaaaggcttgagaaagaggagaacaaaaaaatgctttggggcttaccatatatatggagaaagctaaa tgaataaaccagttgaaagacagcgagttatactagtaacaatattactgatatcggagctctcactt ataaattgtatattatgatcatagtgactaggtactttatatctgctttctcattccttcctcacatt aattcacatgtaggacagattacctcttctgtttctatccagaggcctagagctcaggccctcatcga agacagacagagctatcatccttattctaaaaaaaaactaagaccccagacatagctgtgctacttat agactagaatgtgagagaaaaagacaagctttcatcatgggcttaacaaactgaaacacttcttcaat tttgagattgagaaacttagctaatgctaggtgtaaagatgatatgctaccttcataaccttggtgag gagaaattagcatttctctcagtcctagaaggaggatgaccatgaaggtcttcattctcttgagaaga taatcaaatgcttcactgccctgttaacggtttactcaatattcaccaagaaaagtagatgggattat ttttgcagacacttatacgggtaatttattctgataagcagagacatacctttagtgcataaattgtt ccctttgtgctctttgtaataaacatcaccatagagaacaaacacgaagtaatgacattgaattaaaa gacaccatagaggcaacagcgactggaatttgtgaaagtaaaaggatagtgcaaacagttgtgcgttg cattctgctctgaagattaacaagctgggtcaggctttgaccatcatgatgagcaggagatttttcta atggaaatccccaatcaagttcctgctgcacccagaaaggaacggcttacagaaatcttacatttctt tgcacataccaaattgcttggcatattctatcacaaggtttactttccagggaatgtgatcaagaaat catgatcctaattcctagttaaccctcaaagtttctcagaacagtcagtgcatcactgtcaacttttg tgcaatgtggaaatcagaattggtcacacgtttttccggccactgttttagattcatataatattagt gaaatcatgtcagactggtatagccatgaatttatacttcatgaataggcactcaataaatagtggat taaatcgaccgatttgatttttacctccaataatttcaaaaatatcattgaagacaaggttgttgaag ctgtcacttttcttgctgaacctttgttgtgccaggaggaacagatggtaaaatcaaaagtgattaga gaatcagtggggtgggggtgagattggaggggagaggtcttcccagtgagacccgctagcgtcttccc tgagcagtatgttaacccaagacaattttagaaatctgtgcccctaagttgcttgacatccaaagcac acttgatgcatcctacatttctaaatatttttattgttgtttctcggtagtaatcatctggtttagtc actctaaaagtcaaggatgaaattttaaaatgcaaataaaagtgcctactttctctctttccaattcc tttttgttttattgaggtataatttacatgcacaaaaaaatcgcctttttaaagtgtacagtttgatg agttttgacaaacatatgcagtcctacaaccacgtccgtgatcagaataggaaatatttttatcactt caaaaagtttccttgtactcccgttgcagtcagtctcctgccccaccccagcccctggaaaccactga taggtaaaagcacttttaatctgaaaggtatttaatgtatggcagtgtcagtggtaataataacaaga tttattcattggttcactgtatttttgagcacttatatgtgcccgttgtatgcaacccattatgctca acccctgccctcctcaccagggataaactagtggcagagatagacaaagaagccgtctctctatcacc cctatcttatagaacattcttcaatgttagaaatgcagtataatgtggccattgagaacttgaaatgt gcttagtgggaatgaagaactgaagttttaactttatttaatttcaattaatttaaatttatatagcc acatgtggctaatgactatcccactggaaagtacagcttctatacaatatgataatatgatacattat aacgcaggagtttaaccaagtgctaaagctttactatcaccagggtcactggtgttatgtgaaaagaa aacttacaatagaaaaataaatcctttaaatagtcacagacctgagaaagtttccttctcaagggaac acacattggctcattcaaaggaggttaaaaactagcatttaaggtaatttcatgaagctttcctttgg atttctcatgcttattgtatacataaataggcaattttcgatgggacctaataaatcactgtttttta tttgaacattttaacaaaattatcaaacagcattgcatttatgttcaacctatttgttctgagaaaga caacgattaagtagaagtcatcaaagttaccagaacaatttttgttcttatgttttagaaggcattga aggtgtttaaaatgtacacttatagagtcagagtactatgcaactgtggcccttatagtttatccgtc atgcatctaaagccattgttacatctgtttctaattgtgcatggattgtccaagatacacaattggaa attccattttatttatcaatttgaagaggtttcacccatgtggtcactatgatcactatggagtcaca ttaaattgagaagtctccagaagttgcagtatttatttaaaattctaactttcttcagaggaacaaat tctccatttctggattctgaatcctcattagccataaggttgttgtaagaatttgcagctaataggaa cacatcctggggagagaccagttgaaaagtaacttggttctgagtgaaattatacagagacagtttct acttcaggtggtgttgctaatgaagctatcatggtaattttagcccatatgatccctaaacgacttca gaaccacttttcatccactaagaacccacttcaaccactgccacgttcactaccacagtataatatgg aacaccctctggaattcagtaagtaacttcttaactcattggctatagagctttgcctttgtaaattc tttccttttgcagtaaaagagattgtttcaaagtaatccaattagtccctaggcatgtctagaaaggt agagtcaacaacagtaaggtaatagtccttataagatatgtaagaaattatcagtcatttactttaaa ataatttgtacacttttccttttatatggttcttctatgttgaagccagtggtcatccagtgattaag attagccaaactcaaaaggctaaaactaaattcaaatggtattattttgctttaattttatgcaatgc tatgtatttaaatttcatgaaagtttcgtatggcattgctatcaatttcagtcaggataaatttcccg tgaaataatccacaattttcaactgtacgttgggtacaggtaaggaaacacccttaagagcttatcca gttattagctggtattataaatttcaagtaattcaatgttcaattaataaacagttactttaaatggg aaagtatgagtcaagagttagtacaaaggagaatcttaaaagatgaacatcaaagaatcttactattg atttgttggtgcctttgcttgcacttctccaaattgacttgacgttttaaatttgtactgataatcat cagagtcaaatctgcttttaggcaaaaagtatccgctagttattcccctactatgaaagtgatgagat gaattgatcatgtctccagtgtatggatggatgtctttgaggaagacctactgaccttatgtttatct tctgtcagcatggtgtgactatgtggagagacagtgctatttgctaaatactttgtttttcaaataaa aagatttcacagattatgcattgtagaatttataagtattcttttatgtctttgaatgtgccaataca atttttatgaagttggaactattttatctattttaatgaaattgtaagccttctgtgaattcttttat taattttattctgaagaaaatctgaccaggttagggaaatcaggtcaggttacgacgtgatcccagtg gaaaagctgaactgtggactgtgatttaaaatagggaagaggtactgaagtgttgtttttatttttgt ttacaaatcagcctttctaactattatgtactcccatccttctatctttttctccaccagaacgtatt aacaggcatgcatataattaatgcttttcttgagataatattaaaattaacttcatctgtcaggccgt ctgggctaaaagtacacagtcagatctgggtaacatttgagttgatgtaaatatgcccacacatactg acaatgcttaccatttattgtgtgaatgaaaagcagtgtaaatattgtttgttctactagggaagctc cacattttaatcaaactttgaccgtatttctaaaatgccagagcatctggaattgttaaaggaactga tagtttttgtgtttttaactgttaggatacttgaaatccaaagggtaaagaaactcagctgatttata cgtttcttcctctttattttaatgtgataaaatgtagtttttgtcatgggctgacaaacagtggtaga ctacactaactctgcgtttgctgggtttaatcttaccctctcaaggcatggaatgggagctcacttca gacccagccatgcttcactgtccactgccttctcatggatatagtgtgaacattaattagatgaattc cataaagtgctttaagctctttggagaaagatactcgctgcataattattcttaactcccatacgctc ttatgatataaaccattctcccaggaaatcctttttagggattatcacttaaaatgaaattttcatta ttaaaagcaggaagaatatacatctactgacagacgaaaatgtgcttaaggcgactgcttttaaatag gcagaaatcctgaactatggagccatccatgcctgaaaatactgagtaataatgaaaactggtagcaa atttggaatattaatcatcacattaagttgcaaagaaaaaaaaatacaagccacatgccctttaaaaa tacgtgcacaaatctttattctagaaatatataactttaggcctaaaaaagtacaaaaagtaaattat tttatggctctgaaagtatccttaatttactcaggtgacaacaattagtgtttaaagagttagttttc aatcttagctacaagttggaattactctggaagctctaaaaaaacaaaaaacaaaaaaaaatagagat gcctagttcccacctgcagaaattctgatttgatttttctggtgcgagacctgagaataggaattttt ttaaagcttccctagtgattctagtgtgccacctaggttgccttaaggtaaacctcatattatgcaga acctagcaatcacctatcctgattttatagacgaagatcataagacccaagagggcaaattgatttat tcaagattgaatatacaaatgatagaagattcacataagatgcagtatacagagtggcttgtggattc ttgccaatgcaggcagcagaattttctttagggttcacccagttcaggcacctctttgcagcagcact tgactaaggttcttctgattggatcattatatgggcaaaaagaaaaagcttaattgaaaagagctgaa cccacattgtggaatggaagatatacagtttacacgttataaatgattaatattcatgaaagcatact gccctttcctcttcccttcccatagatgacatcattgcattggtgtagttaggttggtggtttcttgt tgttgatcttggttctgacacagttcatcacttattatcctggcttattatctacttctacattcatt gttcactcactcactaattaattcaacatggtttttattgttttggaccggttatatgcctgcaacgc tacgtaaggctgaggatattacaatgaacaggaaacaaccctgaagtttaaggtatcaagcctttgag ttactgtcttttatcatagctgatataaaattgaagccccactttttttgttttcaattactgaaaat tcagtgctaaaaaaatgtggatttttattcaactagataaagtactacaattaggtttccactgacct tggctgtttttgttcccagttgccattacataaatctgtgccactcacaacttaggaagggtgtaaca ttctctgtaatagtttgcctttcgaatagtgtttggattcattactgtccctcgcagtttggaataat gaccactgaataatcagtgtttggagactaaattagtgctgcaaaattccctcaaattacctactgtt cttttccctgtcgatgtatcctcatattcactatgattaccctgagaagaaagatattgttgagaacc actttacctactcgaagttttggtatttcaaagattcatacttatgtcatgttgattacattagcact aatactattggcagaattctaattcacgttattttctttttttccaatttctctccatgcctatgtgt tgtcccttcgcagctataaagccatggccgattcatgggtgcttttgttaaggcgttcagcagtcacg tttgtagatttttgaatgggacttagagcccttttttgttctttatgtatttctctatttctcagcaa aggaaatgcagacatgcaagaaatagtgatcaaatgtcctgtgtactattgtgggtgtcattaatggt atagggagaaatagaaaatagttgcaaagatgcatttaacaaataaacgaggtcttgagattcaccat gaatgtggccccttctatgaaaagtagttaacatccaactgcaaagttgtactggatcagtttgactt taacctttagctaatatgaaaatatggaattgtgtggtggtgctcacaaaaaagaaaactcatttttc ttaattatcatcaattaacatgtactgactacccatgagggaaagttaatttgctcttgagtggaacc aagaaaaatagataaagcaatttctgattagccagtgaaagcctctaacataaaatttccaaagatgt aagaaaaatagataaagcaatttctgattagccagtgaaagcctctaacataaaatttccaaagatgt gccataaattatccacaaaatgtaaaacttttcaattttggtttgcattttcttttttcttattataa aggtaataagtgctcattatagaatttgaaaaatataggaagttgcacggaagacgaataaaatcagc cataatcctacaaacctattgacacttgtacatatgtttgttatctctaatgcattcattatgataat gcatcttttcaaccaatagagtaatcactggtgactttcaaatttgcctactcatttttcactctgtg gacttactttactacctcttgccctttttcagtaaatgaataaatatttaagtaagtaaatacaaatg taataacttatgcgctcaagcacacagatacacacagagagaatttggaacttcggaaatgccatcct ctccctagggccgcaagtgagttgataagcacgtaaggaaggataatcaggggagccttctcgtattg cccagatggctcaaaattcgtcatctctaccaaacaactatttggagctttgaagaaatatccatgac ccctttgaattcttcagtttctttcgcgttcactttgagaaccaagtgacaagtgaatttcctgactt ggtcttttaaacctgttagcgcagttccattgagattttgtgggcacaagattgcaatgaagagatca acagggagaaattcatttccctatatatgtgcgattaatccggagtgctaagggcagatataaagcag gtgcctactcctgtataacttggaataaaaccatttccaaaggctgatgatcctcaagtcttgttctg caaatgactgatgtataacttcaggccaatttttctccagttagtctgtgtcactgggagtcccattt ctcggggagcagccccatgctttgtcaggtgcggagcccacagaaggttaatgcgaaaagaaggcctc ttgccagactgttttccagatgatacgtagggttattagtttgagctccttaagaagatttttctcac ctgtcctaccaacttatgtttatttcattggtgttagagggtttcagtggcggaagtaaaatatttag cggggaagggacagcgttcatgggaattttgcctaacttaattttgtatctttagctcattcgtagtc attgtactttgtgttttgtcaactgaattttgtttgcatacaaaggcacaaaatgtttgcttcagacc tgtcactcttatttttagcatggttagacaaaaactgagatgctttaattgtctaacttatcccagtt taagtgctgcaaaatctcccaggcaatgtcatgggcaactaagggataaaatcagagatttaaaggtg ccaggtttcccacgcttctaacagttggcgttttgggtgtatacaatccctcagctttcttctttagt ttatggagtcttgtggagggaatagcaggtttttagctaaaattatcatgctgtcgagttgggtctct agtgcatcctgaagagcttgcattatttacagaggctgggctatcattttaaatcctgatgcttcaat gcccgttatcattcttgacaaactcttccagcccgtggtctgttttcctctgtttgcttccatttact ttcctgagcaaccagctgagcaaagatttacataacttttgtttaaacaaaccctgtacagttcactc tttcagccagtatgtaaacacttttgagacacagttacatttttctattttagtcccagattctgttt atttgctacattttttgtgcccacatttttgtctttgttaagtctcttacagattcacatgaaaaacc agaaaccgtggctgctcaaaagtcattaataatgagatttttagctactgtttctgcttgtaaattct tcatttcacataatacagtctcaaaaggccacagagaattcagcctcgcttatctctgtgttgcagat gatggcttctagccttacccaatcccagtgcagcttgcttgccatccaggagtcgaatttgtttccat ctgacattagcgtattaaaaagattggagatcaacaagcaacaatgttcttgtagaaaggtaatcaag gtttagagcctgtgtgtcatgagactcctagcatttgaaaccgctaaggggttgaccaccattgtccc aagcacctgtttaagattctttcctatgataagggacctaaagtgattagcatactgataagattttc ctagaataacctatttatttcagtattattctttcaaatcttaattaccatcttttcctttacccagg gtcttctttctacctctacgacacatttaattacctatattccccaacctgtaccatattaaattttg aatggaagttttatagggtaatttattggaaggatggccttgagtgtcattatgttcaatgaatgccc tattttgacaaagagatgactaaatgttattgaaatctttttaatccaccacgcttctgcttagatgt aaatgcaaatctgttctttacatttgtgattgaattgaacttgaaaagtaccgccatattgattcctt ctgcaaataaaatataattacatttccctaaactttctacactctcccaagagattggctggctttgt attgtagatttttggtgatcacagaggacaatgcattatcataagaccaataagatttatttttacct tggtaaagaattttaatttatttctagtttcattttcatttatatccatctcttctcaccctctgctc tacaaaagtatatatgactatataaattgaaaaaaatatcaagtgcaaaattacagaaataaataatt aggttattttagtggaggaaggtttgttgtgggtggaggaggagaggagtgagccaagaaaaacgagg gaccatacgtgatcatatttttgcagctattttaaattgtttgtgtatatactttaaaatattataaa ataaaattttaagtgcaatgcatatttggagccaatgatgagggataacttcagaaacgtagcatcat catctagtgctttcatagtcctttcaacatttccagatagttttaatggcctgctcatggaggcaatg ccctaattttaacatatctcttcacaactctgatttcttgcttcctaacattaaatgtcttcaaagct tctttcaccactaattccttatcaagaggataagccagtttattctttaagaaaaactagctacacaa aaccgtaagtcattccaacataaatccttcactatcctctctctatagatttggttttgattcctcct gctgaaattcaaccttctttcttcagctatccacacgtcttaccctctaacttccctcaggagtgtct attagctcccattacagtgaccacagtaatatagtaatcccctgctgttctcactctccacttcctta cactgcgttttaagtctcttcatattctttatcaccttgtatcatgcatcggttttcttagttgttta ttttatgttgccttcataaattccatgagagctcactgccgtatctttagaacatggaacagtgcttg gaacataatgggcattccttaaatagctgtagaataaactttcaaaatcaacaataatgtatttgcca aatccattggcttctctgccattttatcttgttcaataccactgcgatattccccttccttttttttt ttttttaaagtctgtaaccctttagcttctgtaatattcctagttttttattcctctcatgtgtcaaa atcatcagttgaggcttattgttttctctttctcactctgacctcacctttgtttacatctcatcttc tggctttggctatcctgttttttatctctgttccaacctgtatttctagccctactacctggacatga catgtggatatctccgtatgaccgcagtttccatatgactttgcaaattcatccctgctctcccctcc aaagtcatccccacaattgacttcctgttccttccaacctattaaggttcaaacccacttttgctcct cctttgcaggctacacttttccttctcagtacctcttttttttccaagttcttagataaaagtcatag taccttacgttgtaattgccactggtctggtctttctgcctgctttcctttccatttgtaatcacatt atccattccaatccatttataatactgtgatcagccataaaaataacatttatcatatcgtttgtctc cttaaaacctgtagtagatcccctctatttacaagatctggtataaaatcacccttcctgatattcaa tgcctgttttaatataatctcaatattatgcgtcataaatccccctgtgttcttgcactttttatttc ttatacatctcatcaaccatgtcttatcaactctcaaaacctgtattcgttttcaggaaaactcataa attattcttttgtagaccttttgtttgtcatctttgaagatctctctctgaactacaatattttgtct gtataatcaatttggaaattcatcaggtattgaaatatgacatgtcttctattgtcttgaacattaat taaaactttatttgactttttatatgcttacatcttgtttcctcacggagtgttaacctactagaaag taatagtttaatcttatatttattttaattcagatttagtagcatactttacacgtggtaggatgtgt aactgccttacaccttgcttacgtgagttattaatgttttcgtatatttaatctgaggatgtactagc aatgttaaaactgtaccgcatgaaattgagtaattgaactatttgttttaaatgtgttgcttaactta ttgtaccattttctcataatcacagctcaagttaactttgtggttgtacgtattatttcttgtgaaat gccaacaaacttagagcaaggaaaataacaggtataatcatactataaaggcaaccttaacactagca tagtctcttagctcatatggtaactacaataatgtacagtgacaaagagaatattgtactttcttagc acacactttcctactactctactgttgtggataaaaacagacatactttaggagaaactatgttattt ccaaataatgccttaaaggttactccaggaaaaggcatttacataaactatctaggaaaagaaccttt taaataatataaagagctcacccaaaaggactgaagtgtttagttgaaaaaaagtaaaaatgtcgaag actttgaaaaatagtttcttgcagtatattttcatcgcttccacttacgttatgaagacattaagcgc tagtttatcaaaaactatttttgtacatgtcttctaatgacagaacaatgtcaacatgattttcatca ttgagaatgcgtaaagaaaccctttgtacagttttttctatgaatgttcccctaagattaaagcaaat ttccaacacgaattaggcactccgaaaggaggaggggagggaggggagcaagtgctgcaaaacttcct gttgggtactatgttcactatctgggtgatggaatcaacagaagcccaaacctcagcatcacgcagta tacccttgtaacaaaccaacacatgtacccctgagtctacattaaaaatagagattaaaaaaaggaaa tcagtatataatctaataaatacctctcaagctttctcatttttaaaataaaattttagattattatt ttaggaataaaataggctcttcattgtatataagttcatttctgagttgcaaaaatcctctctttatg tttttttccccgtattagcatgtttttctcctgtttttccccactcaacttggctgccacaatcagaa agcacaaagacaattttttcttgcgcttgtaaatcaaaaccttagcatcagacaaaataactgctcca ggtctgtcaaatagattcatttgagctttcttcatgcattgaatacggcagaatttctgacctgaaga aatctagccttttccaaatttgctttaagaacattttgcaataaatttaatataataaaaggaaaaaa cacatcaggctagaatttggaaccgattgttattaaaaatctcaagtctatcaatttaacttcaacaa attacttaatttctgtgatggttaatttcatgtgtcaacttggctgggccgcagggtaccgagacatt tggtcaaacattattctgggtgtgtttatgaggctgtttctggagagattcacatttgaatcagtaga gggagcaaagccgattgttctcccttgtgtgggtgggtctgatccaatcaattgaggacctaagtcca atcgattgaagacctaatcaaaaagcctgattaaaaggaactcctgcctgatagctaaagctggaaca cccatcttttcctgcctttgagcttgaattgaaaccttgggtcttcttgagtcttaagcctccagttc tggggctggaacttaacgtcattggctttcttggttctcatgcctttggactcagacaggaactacat cattggctttcctgggtctccagcttgctgactgtaaatcttgggacttctccagattcgtaatgagc caatttattacaataagtctctccctctctggtttcgagagagagagagagagagacagagagagaaa tgagagcacaagaacgtgagtgtgagagtgccctaatataatttctctaaatatcactggttactctt caaagttataaaattggtataaaaggtgacctcaatttttcatggagttaatgtatgaaagtcacaat taaaaaggaagaattagttctggtgtcctgaaagttatttgaataaattaatatgctatggaggcttt aaaatactatgaaaatttaatattgtattattcttagtgttgctatttttaaatagcactttttcttt tcctttttttttttttttttttttttttttgagatggagtctcactctgttgcccaggctggagtgca gtggcatgatctcggctcactgcaagctccactgcccgggttcacgccattctcctgcctcagcctcc caagtagctgggactacaggcggccgccaccacgtccgggtaattttttgtatttttttagtagagac ggagtttcaccgtgttagccaggttgttctcgatctcctgacctcatgatccacccaccttggcctcc caaagtgctgggattacaggcatgagccaccatgcccggcttaaatagcactttttcttgtgagtcac tttttaaatatttgtgcaaaccttgttgccattctactcaagctaatatcctaaaccgaggacattat aacatttcaggagtcaaaacttcagacacttaacatagtatcctcaggttcatccatgttgtcataaa tgacaggattttattcttttatatgactcaataatatcccattgcatatatatccaatattttcttta ttcatccattattaaacacttaagttgattctatatcttggctattgtgaataatgctgcaataaaca tgggaatgcagatatctctatgacatactgattttatttgctttgtctctgtccccagtagtggaatt gctgtatcgtatggtagttctatttttaagttttcgaggaacctccataccgtcctccataatggatg tactcatttacattcccaccaacagtgcataagggttcccttttctccatattcttgccaacactttt tatcttttgtattttgataatagccattctaactggaatgagatgatatctcattgtggttttgattt gcattttcctgatagtgatcttgaacattttttcatatgttgtattaactaagccaaacacagaaaga caaatgcagcttgttctcattcatatgcacaatctaaaaacatcgatctcatagaagcagtaaatgga cggtggtcaccaaagaatgggggaagtaggggaaaagcgagaatggggagaggattgtcaatgggtac aaagtcacgattagaaaggaagaattagttctggtgtcctgttgcatagtatggagactattgtcaac agtaaggtattgcgtatctcaaaacggctagaagagagggttttgaaggtttctaccccaaataaatg gtaaatgtttgaggtgatatgctaattttcttgatttgatcaagtaaaggtcttaattgtttggcaat taagactcatgaatacaaataaaggtcttaattatttggcaaagcatgctgagttttgtaaacaattc agtagtgatttttgagaataggtcaatagcaaatattaattaaaatgtcttctatttatgacctacag ctagatggtaaacagatagatgatagatagataactgatagataactaatagatgacagataaatgat aaatagataaatatagataatcgagagagaatacctttcccttcacacacgtgcatataggcacactc catttctatcatagttaccaggattcagacattttgtctcactatttttctcaatgtgaacatgcata taggaatattatagtttttgttctgtgcccattttagttcgttttttaatatttcaggacaaaggcaa tatggcggtttcactttgtttttcatttttgcttatactttttaaagctcagtgtagaaaagtttgaa aatacacaaaagtattaaattaagacagctgggcacagtggctcacgcctgtaatcccagcacttcgg gaggccaaggtgggtggatcacgaggtcaagagatcgacaccatcctggccaacatggtgaatcccgt ctctactaaaaatacaaaaattagctgagcatggtggtgtgtgcctgtagtcccagctactcgggagg ctgaggcaggagaatcgcttgaacccgggaggcagaggttgcagtgagccgggatcacaccactgtat tccagcctggtgacagagcgagactctgtctcagaaaaaaaacaaaacaaacaaacaaaaaagcacct atagtctttctcccataggttgccttcttaatgggttttacaccttttgatgttttcttgagttctgt cccattagcaagtagtattgtacaaaaaaaattttatcatcttttatttaatattttattgatgttta ataattagaattattttaaattttatatgtcattttaaaatgcaatacaatatagtaaactcccagat gtgattgtaaataattaattattctcccattattgggcattgggactgcttccacattttggtcactg cagtgaacatccttgtacatgaatctgtatgttgaagttgatttcattccacactccccttcattcaa ggggctccaaccattctcgttttctttcagcttctttatatccaggcatataaagttccttcctgact cgggagcgtcatacatgctgttttctccatctggataagtagttaattctgttcttctttgtgcatct cccgtttcagtaacttcatctccaaagcctttccaggtcactttatctaaagttacaccataatcttg caaatcctcaactattgagcattattagtctccgttatcattattctccattattctctgtgaaagca tcccgtgattttcttttgtccctattaccacaatatgtgtttattccgtgtatgtacatctttgtttg tttattgtttgtctatacctgcaatgaaatgcctaaggtcaggaactgtctgatgcaggatgcaatgc gctcaataaatatttactgaacaaattaattcatttgctcagtcttgcaggcaaatggtacttctgta tatttaaatatctaaaatgaaagcgttactcgttactgttggttgtcaatcaaaatttaaatgtcgat gtttaagcgtgaaagacctctgtcaagttaatctgtacttacccaaaggctattatgtagaagcgaca taaatattttcctaaatgttgattttcatattttaagaagacaatgaatgtttcaaagcattttcttc tacacagctatttattctggagagtggggcatatgtttcttaatattgttaaaattggcaaggggata ctgttgctatatacaaagaacacctaatcatcatgcagacgttttgtttctggctctcagttatgaaa agcagagattttaaaaagttacctttatatgctaaattaggaatggcagaaggtaatattctaatgtt tataagtggttcttctctgagtccttggtttctatgtttatgaattctctttttgaaagaaattatag ttattattaccaggtctattcttttacattgtttctaattctatggtgatcttcaaaatagagtatca attttaaatacttgggaatgaaattattcttcccatatcatttctttgtatggcatacattgtgattt gttgtcccatcattgtttcagtatgacctgttactgcaaaaacatattgagataaatcatcccacata ctctcggccaggacagacatcacactgttgcagcaacacttcagatgagccccattcaaccttgtgtt tttatagagaaggatgccacatgtttatattcatttctgaagattggctcatattatttattgaaaca tactagtttaaaaatctgtccatttatataacacctggtctatctacataacttgaattacataaata taaaactaaacttcccctcttctccagtgtatagcttgcaagcaagtgcatgtgaaataaattaaagc cttgtttgtgtttttttcatcatgtgagtacaagacttttcaataaaaatgaattacttttgaacata tttgtttggacaacaaacaagagaaaagatctatttgattgatagtggacagaattttcattaagttc aacagcagaaataccacaattgcatcattcaccttcgtgtatcaaaagaaaacagaaaattagatgtg atgaactctacacaaatgttcactatgcatactttacccattaaatacattatcaagaatcatgtcag catgacattctaatatagcagctttacaaaaacatgtaatctaatctagggatgctgttgtcctcttt aaatcagcttcaaacatattctgggttgatatttctcattcttttttgatccacattgtttattcaca taatgattatatttaactgaagataacagcattatcaaagtgaaagacaaaatagatgtttaatagga aagtgagtatcgaatcatcttttttctaccaaaaacatctataattatgaagtatttggttaattatt ttcacaataatttaaaagtgtacaacttgccgatttttttgtactttctacttttcatgtctcgcata tatctctttaatatctaagtatttgagtcagaaaagagccagtaccgaataatgggaatctcactgaa atgtgataacaatctggggcctggtcctgggacctttatctgcaggacaacttggacaaatatttaga cccccaattcctcgtctttaccctaggaataataacacatttttctgacctcatacttcacgtggatc tcaaatggaacaatcatctgatagcactttatgaagtatatgaaagcaataaattatcacaataagat aattgcaattattctttggcatagtattagtgatgtctttatctgtctgacaaaatcaacatttctgt 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aaagactattttatctattctctcactcttgaataaaaaaatccagaaaaaaataccttgttttggta agattatatcaatttatttcccaaatgggtagagggttatttttttctgatcataaacgtatgtctct tcattataaaaatccactaaaagtgatagaagaaaaccaaaagaataaatgtaaacaatgatgccatt ttccaaaaatcaccttcgacatttttctggatattgatacagtctaaatctcttttcggaagactccc tcctgtgtaggttccccaactactctgcaatcttatttcctcttgttctgttcttgtagaaaggagac ccattgtcaccatgtcaaataacacaaaatggtgcacgtataagatcattgtctctgtccattatttg ccagaggacctcaaactttttcaggtggtgggcaactggatgtcatgctgctccttgtacaacagaac acaattcattatttatatggttatttcattttaagaaaatttaactttcattagctggaaaaaaaaag aagtggtttttaagttgtttagaaatgtgaaattcaattttcatactgcaaaagagattcaactgcaa acacaggcacacatgtctggtgtaagaacgagttgtcatacaaacccaaattagctgcctccacgttg tctttgttaacaagtgtttgtttgctccttgttccatcattcagaaatgctctttagcaggaattgat ggaacacagtcgcagtgacctcttcctgtctttaaaaatcgagatgacatttgcccatctgcagtgtt aacatagttcctcaaagaccactgacagtggggtaggactgtattgcgcaagttctctcatttcccta gaatataattggtccagggccagagattttagctcatttagagcagcaaggtgctcttttaaaattcc ctcacctattttgggcttcatttcccttatacggttatgccttttccagtctgatgaacattctcctt gacagagcagacaagcaaaaggagctgcacactgctgctttctgtgtcgtctctatccctaaccttct cccttctgccccaatcagtgaaccttcgtctttctggttcttcttcctccaaatggaagtaaaaaggc cctgaatgttgtctttaccattatcacgagcctcaattcattccaagctcagcttttcctcactgttt atacagttctatattgttcttctaatatttgccctcagttctctgtccctcgtttcttcccatgttca tactctattagaatctgagcacctttgaggttgtccatacagtggcacacatctttgttttatactca ctgggatgatttgccattatattgtcaaaattttattctaaagagcttttacaggctttcttgagcca ttttctcttgaaattcaagatcgttgaatctctacgctttttccttcttaatctaataaacatacacc cccacatacacacgtgtgttcctgaaagacagatgccacttgactcgtcttatagattgtctaaattg atcattgtgtgtggggataaaagggtgaattgtataatatccctgatggttcacgaagtctgttcctg tataacctgattagtcttctgaactcttttaaattctgtctgcaaatgactgaggtttggcaatcagc ctatttcagttagttgttttcttgcataagaagggtccatatgtactgtgtgaagtaagagagagaaa gtacttagatttgctggatgccctgattgttagcatggctaaggtattgtgtaagtaaggagagcagt taaaaatgatattgtttttatttcttaattgaggtaaaattttatataagatgaaacagacttatttg ggagaggaggaagagtttgttcttacataacatttcaacctgtcatatttagttgagaacttcaatct gtcaagatactttgtataatattcagattctgccatctaatatattttccacgctttcttactgggtg tgacagtaacttatactgtggcaggtgtataagttagtaaagatattaaatgctcaatctgttaactt ttgtgaagtggtcccactgataaagtgacacctcaataaaataaaaatttccattacctcagaaagct ttttcatgctaccttccagtcaattcccagccccaataggcacctattcttctgatttatatcaccat agattagttttgtctttttaaaaatttgtataaatgaaatcatacaaaatgtactattttgatcagca tactacttttgagattcatccatgtaagtgtatcagctgttcattcctttattgatgattaatattct attgtatagatataccacaatttatttatctattctccttttgatggacattcaggtggttttcagtt tttggctgttatgaataagatgctgtggacatttgtgtacaagccatttgtgagcatatgttttcatt tagtttgagtaactctgtagaagtggaatggctgggtgaaatgtttaaatttatgagatattgtcaaa cagcacctaaacagttttctaaagtggttgtgccattttgcaatgccaccagtgatgatggagagttc cagttactctacatctttgtcaatatttggtcttgtcagtcattttaatttttgctatcttacagaat atgtaggtatattgttgtggttttaacttatattcctctgattactagcactattaagcatcttttca tggatttattggacattcatatagattatgtgtgttgaagattattacctttatgattattgggtgaa aatagtatcattttgaggtcattcatataacttgaagactgggaatgacagacattttcctgttttgt ttcttttctttttactttatctgaagagtctactagaatgcagtgttgctgcctgagcagcagggcat tagctttgtaaaagctctgttccttggcaaccccaccactaatatgaagtgcagaacatttgaattgt ctttgaccagcttcagcatcagcactattttttttttttgctagacccctagtaggtatttaaaagta cagaaatagaatttaatcatgctttttaccaaatgtgctatgctcttagagattctttcaacgtgcat aaaaattctgcagtttcaccacataccagtaaaagaaactcagtcactcatttagccatttagtaaaa agaacaaattaactgatgagcatagtggagacctcaaaggtaaagaagacaatgtccctgaaataaag acaatcataaattttcaatcaaaataatgaaatttaggctgggcatggtggctcatgcctatgatcct agcactttggaaggctaaggtgggaggattgtttgaggccaggagttcaagaccagcctcagcaaaaa agtgagaccctgtctccacaaaaaaattttaaaaattatctgggtgtggtggtatgcaccggtggtct cagctactcaagaggctgaggtggaggatcaccagagctcaggggttggagactacagtgagctatga ttgtaccactgcactcaaacttgcatgacagaatgagtccttgtctctaataataacaaaatttaatt tttatagactgtgaaaaaccattatgtagatacagttcaagtacagtatgattttataggatagataa cttttgcttgaaaatgtattcccaatttataggatagataacttttgcttgaaaatgtattcacaata gagttagtatttggggcacacctttatccatttaacaaacatgttttgagcactgccaggtagcaaca cgttactaggcactagagtgagaaaagattacagttcctgctctcatggatctcatggtctagtcaac tggaatgaaaggattacataagtagaggtaaagacacacatgatggaggatggagaatagtcaaaggt ctggagaatgaccaggacgtcactgtgagttgtctaattgcactgaagcatggatgaagaattggaaa gtcattgtaagaagcctaaaaaggtatctctcagggatgctatgaggttctgaatgttatgtacgcta tttgggcttcaacaggcaggcactgagtattcagtataaatttttgagcagggaatccaccagaagaa ctatgcatctggaggattaatctggaaagattgtgtagaatgttatgcagtgaaagagtctgagatga aacagttaggagggtgtattaataacataggtgaagtgtaatgaataaccaggctggaggaaaagcaa taacgatggaatcaaccgggcaagaagtataacaattaggatcagtaaaatagaatttggattggagg aatgaaaaaaaaagggacaaaacaaagttgaactgctggtatccatactggaaaatacagatgtcatt caaataaataatgtaatgaatataagaaaccagttttaggagtgaagtggatgttggcttgaaaatat ttcctttgaggtttcagtcaaatgaaaaggtcctgaaatgctacgtggtagcctaagaaggaagcgtt cctagagagaaaaaaattagaaaagatttacatttgataatttaatcttttccttcatacaagctaaa ttgataagaaagtaaaacctatagttttcaccactcttttacaaatatccctaaccttttagatattc 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acagcattttctagggtgtccccattaagttgagagtgttgacaagaaaatacaagcttatttatcat tgtaaaacttgagacacctagtagttaccctaaattaaatatttgttggagtcagtcacactaaagag aacacttactgcattgaacaatttacctacattagacagcatttaaagactatgccacagcaaaggcc catggaattcttgtgaacacagaatagaagtgtattaaggaacaagcttaattctgttctcttaaagc acaacactttctcaaaacatattttgaaatcacctttgaccattttttttaactaataggtgggtggg agttagggtaggaaaacacaagcagcttcatcaaaacgatattctattttcttcaaatttgtggggaa tcatacggcctctcaattttctacattatgctaattatgatattaatctctctgccagcaaatgaaaa taatacatattagatgtagcaaatgtcaataatgacaaaattagtcatcatgcagatactcagggatt cccaaaatatgtttggattatgattgctagctttgagtttgcccagaatcgtttcaataaaaataagg gactcaaacacatttggagcaaaactcacatcataaattttagacatagctctgccaataatgctctc agttatattttcagtcctaatatttcctctgagttccagaccagtatcttcaactgtctgattgatac tctctccttcatttctgtctccaatgcattaagtcctgtgtatttactttccaaatgccacttggttc catgcacttctctccatttctgccactgactcctcctcaatccaagcgaccatctttcctcactttaa ctaccatgatatctcctgcttggtctccttacttctattcccgggctcctccaatccattcatcctcc agcagagaatgatgactagcaccttccacagtgtctggctaataggaggtatccaatcaataattgac ttacagagtgaaaatataggcatggcaaataccagtagagaactacagggttttagaaccaatgacat tagatacttccatcaaatatttacagtgtataatcaagttgacttgcacattgtcttatttttgaaaa acaattttgttggctttttctatatgcacacatacatattgtatcaccctctacccgccaaatggctt ttgaagaagtatttatgtggctccaaattgataatacctctagagagaagagaaattagaaattttaa aatgacctatgcttcctttcgaatatcacgtcctgagacagtgttttttgagttacgtgcaatatgtt ccacgatgaaacatttaatgtgttcagaggcatgctagtaatcatgtagaaagaattttatgcctgaa gtcacatgttctataaccaggatcacttaataagaaaacaagtacagctgtggacaagatgccttttt atcagggaaaggccaatttgttttctttgcaaatctaagtaaatggagagaaaaacacagcccttaaa tgttttctatttgtcctgaagttctcatgaatgagttagaaggcgagaaggattaaataaatccttga acgtagagagagctaacatttattttagcaaactaaaacctattcgctttgcaaagttctgttctgta ctttgtaacaacagttttctttaaaacaagagccaccaattcaaatgcctttacagaatgattgaatg ctttcatgccccacctaaaggcattcaaatcattaatcaaacaaagttctaacgccaaaacatgtctg ggaccagatttaaaatgtagccctcagtttcagagggcaaaaacttaacatatttatattttcctcac tttaggtaacactgtattgaatctctgcttgaaattgaggagcacgtgattttttctttttggcccag ggcagcatttcttggaagagaaagaaaaacaacccaagatacccttacaaaacatgtagtacttaaag ctctttatgatgaattaattttggtatacacattaatagcagtgataataacaaatctatatatatat atataattgatatgaataagataaatacatcaaaaggaaatttcattacaatttgatattaggtaaat gtcccattaaaataaattgctactgtacataattttccttcagttcattggcaggatgtttgctttgg aaaataaacagtctatttctagttttagaaggaattctcattattcttttatagcaaccattatcagg agcagatgggaaattgtaccaagagcatatctactattatacctcacaggaaaaagagagtattaaat gaaatctaacaaggcctgctcctgactctagttcctgtaacaaatgaacacacacatttgtatggttt cagcatttgtattagtaaggtacaataaatgtttactgaaattgaaaaaaaaaaagataacaggagaa agaagaggctaaaaaggtgcattttatttctgatcgttcattgtaaagactgctcctttttaaaataa tcaaattttattttatatacagagggtacatgtacaggcttgtcacaggggaatagcgcatgatgctg aggtttggggtacagatctcatcacccaaacagtgagcatagtacctacctgatgagtagtttttcaa ccaatgcgcaccctccctccttcccacatctactagtccgcggtatctgttgttcgcatatttacgtc catatatgctctatgtttagctcccacttataagtgagaacatatagtgtttgtttttcctgttcctg cgttaatttgcttatgattatggcctccaactgcatccgtgcttccgcaaaggacatgatttcattct ttttatgactatgtagtatttcatggtgtatatgtaccacattttctttatccaatctaccattgttt cacaactagatggattccatgtctttgctattgtgaatagcacaagacaggacctttttatttgactg agttccttgcaaattactaataaaagatctggaggtccttagttaaaagttgaatctgtagtgccgtt caaatttagagatgtattttctgttcaagagaagaaagccctcattcggtcatgcttaatattcagct gtaaagtccaaaacatatgagaatgacacaaatggaaacattttataaatacctatacaaaggagggg cacttagttcccctaggcctcttaaaagtcctctagaaagagggtacttttatgctaactattaaaga tgagtaacgaatttgtcctatacaacttaacagtatcgtcaaggaagtagaaagttactcagttttac tgggcattggagctaagcttgaaagtgaggaggagaagcggcaggagacggagccgagaaggcagtgg ggagaagaggaggatggtcctttccatgctccctgttgtactaacatgtttggatattatcttatact tcatatatggactggattcttgtccttctcattctgagctctccttgaccttgattcttacctcctat aactttcattctttctttactcaaaaaaaggccatttatttcagccatttttcactgttttcttatcc ttcctagttgcttttctatactatttttccactcttttttttttctatactattttgcccttctctcc attttcctaactgctagatttccccaattttagccatctttcaattgttctgactatcctcaggtgct cccacaaggttatcagaccttccaccaagacggaatccctcagtctatggacaggctaagttgaatgg gtcctggtgctgtgcttagcatatgccttgagtatttgtgcatttattttgcttctttacaaaaatcc atcatccgatagaagttgaaagaaacttgctgaagcacattaaaatctctgaaaacagtattggctat attttctaataattagcatgactggttaacttgctttatttatcattgaaaaaagtatcagaaactgt atatcaaactcctgaattcttggcactgacgaagagacacaatgagaatgaccttaggataaaaaaac aagataaagcaccatatttgtaggaaattgcaccataaaagtctgtttcacaactctcccaaatttca ttttattacatcttttctcttgaccaatcagtaaactcggttaatgatttacctgtctcaaaataatt catgaacaaaattacaagtaaatctcagtattggattcttgaaacatctccttgttcaatgaagtttc ctttttcttccctctatttccctgtatttatcttttcttccagttgcattttatctcttctgtttttt tatcttgctccctagtttgtgattttttgccaattttttatttcctacataattcatccaatctgtca ttgtacaatttcttataactgcttcttagcttattccttttcttcatttgtcacattctatttttcat ctattgtgttttcatgcagttttggaaagttttacaaatagacttttaaaaaaatgtacgtaatgttt tcatagaaaaggtagtggtttctttttcttatatccttccctgtataaaaataaaaatgtagcagttc tttctttgcctatgtttcctctttccttcccccaatttgaccagacttgaaggacttagatatgtaac agtgttattttctataatttaggaacagcttttgacttaaaaagcagaagagaagttgaaaataatat agtaattctacatgtccttcctgcttcccaactctctgcacatgtttgtaacctcccctttctttttt agtgtatctctttcatatacctttgtccccagaaattctgattcagtagacttagaatggaattctgg gcttttatattttgaaaagctccccacgggagttagatatgcacttcttattaagaatgaatgcttaa tattggaatcaaaacacaataagctttctaactatgatgaataatccaacagatttaattatgatttt ctttttgtccagaaccaagactagatgttaattgccagagaaatagataagaatgcctatgacagcag tacattaatatgatatcaaagcttggaaattttattggtaatgaataattcagtacttaaaatattta gaagctatagaattaaaattaattaatgttgttcactgtgtgaataaagttgattgagattttacatt taattttgtaaacccagtgttatcttttccagctcagaaaacaccacatacaagctactactttctgt tttgatcccttatttttctttcttatgctttatcactgaaaactctccttgagcaggccatgcactgt aaatatttctcctggttgcaaaaccttctcatacaaatgcagtagactgtgtaatgagctcttctttc acaaaattaaaaaaacctgaaagccctgatttgcgattctatacaaatgagatttagatctaacaatt ttaaattattgcttcactcttagctgttcaattctatctcttatttgggaaaccgaaataataaaacc attgctgattccacaattaggttgtaaaagtcaccgtagccatcagccatgaagcaaaagtgccaaga tcaaaactacaaagcaaagaggctgagataaaaatgctgcagcattagtttatagcattataagcagc aataagaattccttgattgcttaacaaagactcaaaaggcatttactccattaccttacaactcaaag aggtattcctggaccagcagtattggcatttttttgaagtttgtaggaaatgcagaattttggtgcct ccacggacctaatgcagcagaacttgcagtttagtaagatctccaggagatttgtatgcgcattaaag tctaggaagcaccgctatggtatacatctgatgtgtgcccatgcattttttaaaagtatgaagtaata gttgtaagtattggacactcttgaaggaacaaataagagccatggtctttactctctaaatacctccc tgacatctatgttttaggcaaaatttttttcccatttcagtagtcactgatgcttgcacgatgcagtt tattccaaaacaatggtgattctcatgtaatagttcatgttgccttaataatttacgttgcctcaagt tctctgcccaggccccaatatacaccgagggctgtactcctcccctaacgcctgctctcatacagtgg catagagcccagttttatgctcttggtcacatcatggagattgcacaccacaggctttaacttctgcc gtactctcactgcctctaaccctccatatgcctaagttctacgattctttaaattccaaattgaccca gaagtctcctccgctcatccttttcactgagatcatccctcttctggcctaccatttgttgatcacct tgctttttttttatcctactgtatgtagtataacaaattatcacttgcaactgtgtcttattttttca actagattatgtactgcctaagacctagaaaattgtgcttatttatttgaatctctaggaggatcagt aatgggtattaatactaatgactccatggtgatgatgagcctgaacttcctcccttcctttctttcta cctctctcctttcctcccttcttttcttcctccattccttcctctcttcctccctccgcttcttcccc acttcccttattcatagattcatgcgttcactcagcaaatgcttactgaaaccttccatgcatcagac attgtactaaacaataggaaactatcatgaataagacacaatatctgacctcaaagaatttatgatat aaaagtaatggcataaaccgtgattacttttgcaccaacctaatatatagacacagtttgttatgact ggtgtctctattactaagcaatgactgtcacatgcaacgctgatctgaacaggtggtaaagagtgaga tgtaagcaatggagcaaagccaactagttacaaggaaatatcacatgtttactagagcacatctcatg ggcattcaagagagtatggccaggacagcttgtgaatagttcagtaactgtgcatagttttatattca ttgtgaggcaccgtgtcaccggtttgctgatttacagagtattttaattgctaactgtatgctaccaa aatttccagtattcgaaaataattttgcttgaatgtagaaaaagaaaaaagccaagaaatgtatgtga aacgagagtctaagggagctttacctcagtctcagaaaacatgcattccttccttcatttaggaagca tgtactggggtctactgtcagcttgctattgtgtcaaggagtaggagaatacaaaaatattagagaat atgaatcacatctattaggagagttttctacatacgcacattattctgtcagtgacataaggatttga gtcattcagatttaaatacggtaggtacctcaagttctcagatattatttcattttctaaggttcgta tttagttaatatgttattttaatggccttacaaattctagattatcttttttaaaaagttaaatagaa cgtaattgccatttttatttaatggtaaaaagcatttttgtttttgtgtgtacttggttgtaatattc tccttttcaattgagctatttttctgatactttactcttaaaatttcattcaggaaaaaagtaaacaa tatttaagcttgacaatcataaaaatgctctggtgactatagattattttaaaatttattactgtagc ttagggatatcttgatgggatgctcctgaaagcaattaattctcagttttttgtggcttctaatgcaa aatacattgacgcagacagaatttgaaatgaattttcttctaatatagcaattaattttatttaaata tctctagagtttttttttaatactgtgactaacctatgtttgttctttttcacctctcgtatccacga tcactaagaaacccaaatactttgttcatgtttaaattttacaacatttcatagactattaaacatgg aacatccttgtggggacaagaaatcgaatttgctcttgaaaaggtttccaactaattgatttgtagga cattataacatcctctagctgacaagcttacaaaaataaaaactggagctaaccgagagggtgctttt ttccctgacacataaaaggtgtctttctgtcttgtatcctttggatatgggcatgtcagtttcatagg gaaattttcacatggagcttttgtatttctttctttgccagtacaactgcatgtggtagcacactgtt taatcttttctcaaataaaaagacatggggcttcatttttttttgcctttttggtatcttacag DNA encoding gRNA gRNA GGGGCTCCACCCTCACGAGT GGGGCUCCACCCUCACGAGU (SEQ ID NO: 157) (SEQ ID NO: 171) GCACAAAAGTCAAATCGGAA GCACAAAAGUCAAAUCGGAA (SEQ ID NO: 158) (SEQ ID NO: 172) GATTTCAATATAAGATTCGG GAUUUCAAUAUAAGAUUCGG (SEQ ID NO: 159) (SEQ ID NO: 173) GTGAGGGCTCCACCCTCACGA GUGAGGGCUCCACCCUCACGA (SEQ ID NO: 160) (SEQ ID NO: 174) GAAGGATTGAGGGCTCCACCC GAAGGAUUGAGGGCUCCACCC (SEQ ID NO: 161) (SEQ ID NO: 175) GGCTCCACCCTCACGAGTGGG GGCUCCACCCUCACGAGUGGG (SEQ ID NO: 162) (SEQ ID NO: 176) GTGAGGGCTCCACCCTCACGA GUGAGGGCUCCACCCUCACGA (SEQ ID NO: 163) (SEQ ID NO: 177) GGGCTCCACCCTCACGAGT GGGCUCCACCCUCACGAGU (SEQ ID NO: 164) (SEQ ID NO: 178) CACAAAAGTCAAATCGGAA CACAAAAGUCAAAUCGGAA (SEQ ID NO: 165) (SEQ ID NO: 179) ATTTCAATATAAGATTCGG AUUUCAAUAUAAGAUUCGG (SEQ ID NO: 166) (SEQ ID NO: 180) TGAGGGCTCCACCCTCACGA UGAGGGCUCCACCCUCACGA (SEQ ID NO: 167) (SEQ ID NO: 181) AAGGATTGAGGGCTCCACCC AAGGAUUGAGGGCUCCACCC (SEQ ID NO: 168) (SEQ ID NO: 182) GCTCCACCCTCACGAGTGGG GCUCCACCCUCACGAGUGGG (SEQ ID NO: 169) (SEQ ID NO: 183) TGAGGGCTCCACCCTCACGA UGAGGGCUCCACCCUCACGA (SEQ ID NO: 170) (SEQ ID NO: 184) 

1. A CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.
 2. A CRISPR/Cas-based genome editing system comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.
 3. A CRISPR/Cas-based genome editing system comprising one or more vectors encoding a composition, the composition comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.
 4. A CRISPR/Cas-based genome editing system comprising: (a) a guide RNA (gRNA) targeting a fragment of a mutant dystrophin gene; (b) a Cas protein or a fusion protein comprising the Cas protein; and (c) a donor sequence comprising a fragment of a wild-type dystrophin gene.
 5. The system of claim 3 or 4, wherein the gRNA hybridizes to a target sequence within intron 51 or intron 44 of the mutant dystrophin gene.
 6. The system of claim 1, 2, or 5, wherein the gRNA hybridizes to a target sequence within the polynucleotide sequence of SEQ ID NO: 128 or SEQ ID NO:
 156. 7. The system of any one of claims 3-6, wherein the donor sequence comprises exon 52 of the wild-type dystrophin gene.
 8. The system of claim 1, 2, or 7, wherein donor sequence comprises the polynucleotide sequence of SEQ ID NO:
 53. 9. The system of any one of claims 1-8, wherein the fragment of the wild-type dystrophin gene is flanked on both sides by a gRNA spacer and/or a PAM sequence.
 10. The system of any one of claims 1-9, wherein the gRNA targets an intron that is between exon 51 and exon 52 of the mutant dystrophin gene.
 11. The system of any one of claims 1-10, wherein the donor sequence comprises multiple exons of the wild-type dystrophin gene or a functional equivalent thereof.
 12. The system of any one of claims 1-11, wherein the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of the wild-type dystrophin gene or a functional equivalent thereof, or wherein the donor sequence comprises exons 52-79 of the wild-type dystrophin gene or a functional equivalent thereof, or wherein the donor sequence comprises exons 45-79 of the wild-type dystrophin gene or a functional equivalent thereof.
 13. The system of any one of claims 1-12, wherein exon 52 of the mutant dystrophin gene is mutated or at least partially deleted from the dystrophin gene, or wherein exon 52 of the mutant dystrophin gene is deleted and the intron is juxtaposed to where the deleted exon 52 would be in a corresponding wild-type dystrophin gene.
 14. The system of any one of claims 1-13, wherein the gRNA binds and targets a polynucleotide sequence comprising: (a) a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (b) a fragment of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170; (c) a complement of a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a fragment thereof; (d) a nucleic acid that is substantially identical to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, or a complement thereof; or (e) a nucleic acid that hybridizes under stringent conditions to a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, or a sequence substantially identical thereto.
 15. The system of any one of claims 1-14, wherein the gRNA binds and targets or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, or a variant thereof.
 16. The system of any one of claims 9-15, wherein the gRNA spacer comprises a sequence selected from SEQ ID NOs: 29-51, 87, 157-170, a complement thereof, or a variant thereof.
 17. The system of any one of claims 1-16, wherein the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 64-86, 88, 171-184, a complement thereof, or a variant thereof.
 18. The system of any one of claims 1-17, wherein the gRNA binds or is encoded by a polynucleotide sequence selected from SEQ ID NOs: 35, 40, and 44, or wherein the gRNA comprises a polynucleotide sequence selected from SEQ ID NOs: 70, 75, and
 79. 19. The system of any one of claims 1-18, wherein the donor sequence comprises a polynucleotide sequence selected from SEQ ID NOs: 53-56, 154, and
 155. 20. The system of claim 19, wherein the donor sequence comprises a polynucleotide of SEQ ID NO:
 55. 21. The system of claim 19, wherein the donor sequence comprises a polynucleotide of SEQ ID NO:
 56. 22. The system of any one of claims 1-21, wherein the Cas protein is a Streptococcus pyogenes Cas9 protein or a Staphylococcus aureus Cas9 protein.
 23. The system of any one of claims 1-22, wherein the Cas protein comprises an amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:
 19. 24. The system of any one of claims 1, 3, and 5-23, wherein the vector is a viral vector.
 25. The system of claim 24, wherein the vector is an Adeno-associated virus (AAV) vector.
 26. The system of claim 25, wherein the AAV vector is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV-10, AAV-11, AAV-12, AAV-13, or AAVrh.74 vector.
 27. The system of claim 26, wherein one of the one or more vectors comprises a polynucleotide sequence selected from SEQ ID NOs: 57-60 and 129-130.
 28. The system of any one of claims 1-27, wherein the molar ratio between gRNA and donor sequence is 1:1, or 1:5, or from 5:1 to 1:10, or from 1:1 to 1:5.
 29. A recombinant polynucleotide encoding a donor sequence, wherein the donor sequence is flanked on both sides by a gRNA spacer and/or a PAM sequence, and wherein the donor sequence comprises one or more exons selected from exon 52, exon 53, exon 54, exon 55, exon 56, exon 57, exon 58, exon 59, exon 60, exon 61, exon 62, exon 63, exon 64, exon 65, exon 66, exon 67, exon 68, exon 69, exon 70, exon 71, exon 72, exon 73, exon 74, exon 75, exon 76, exon 77, exon 78, and exon 79 of a dystrophin gene.
 30. The system of any one of claims 1-28 or the recombinant polynucleotide of claim 29, wherein the dystrophin gene is a human dystrophin gene.
 31. The system or the recombinant polynucleotide of claim 30, wherein the system results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.
 32. The system or the recombinant polynucleotide of claim 30 or 31, wherein the donor sequence comprises a polynucleotide sequence comprising exons 52-79 of the human dystrophin gene.
 33. The system or the recombinant polynucleotide of claim 32, wherein the donor sequence comprises the polynucleotide sequence of SEQ ID NO: 55 or SEQ ID NO:
 56. 34. The recombinant polynucleotide of claim 29, wherein the recombinant polynucleotide comprises a sequence selected from SEQ ID NOs: 57-60.
 35. A vector comprising the recombinant polynucleotide of any one of claims 27-32.
 36. A cell comprising the recombinant polynucleotide of any one of claims 29-34 or the vector of claim
 35. 37. A composition for restoring dystrophin function in a cell having a mutant dystrophin gene, or the composition comprising the system of any one of claims 1-28 or 30-33, or the recombinant polynucleotide of any one of claims 29-34, or the vector of claim
 35. 38. A kit comprising the system of any one of claims 1-28 or 30-33, or the recombinant polynucleotide of any one of claims 29-34, or the vector of claim 35, or the composition of claim
 35. 39. A method for restoring dystrophin function in a cell or a subject having a mutant dystrophin gene, the method comprising contacting the cell or the subject with the system of any one of claims 1-28 or 30-33, or the recombinant polynucleotide of any one of claims 29-34, or the vector of claim 35, or the composition of claim
 37. 40. The method of claim 39, wherein the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.
 41. A method for restoring dystrophin function in a cell or a subject having a disrupted dystrophin gene caused by one or more deleted or mutated exons, the method comprising contacting the cell or the subject with the system of any one of claims 1-28 or 30-33, or the recombinant polynucleotide of any one of claims 29-34, or the vector of claim 35, or the composition of claim
 37. 42. The method of claim 41, wherein the method results in a dystrophin gene that encodes an in-frame transcript comprising an exon 51 joined with an exon comprising a sequence of SEQ ID NO: 53 or SEQ ID NO: 55, and with an intron therebetween.
 43. The method of claim 41 or 42, wherein dystrophin function is restored by inserting one or more wild-type exons of dystrophin gene corresponding to the one or more deleted or mutated exons.
 44. The method of any one of claims 39-43, wherein the subject is suffering from Duchenne Muscular Dystrophy.
 45. A genome editing system for correcting a dystrophin gene, the system comprising a donor sequence comprising exons 52-79 or exons 45-79 of the wild-type dystrophin gene.
 46. The genome editing system of claim 45, further comprising a nuclease selected from homing endonuclease, zinc finger nuclease, TALEN, and Cas protein. 